Antiviral method employing 1-sulfonylbenzimidazoles

ABSTRACT

Certain carbonyl-substituted-1-sulfonylbenzimidazole compounds are useful as antiviral agents.

CROSS REFERENCE TO RELATED APPLICATION

This is a division of Ser. No. 94,149, filed Nov. 14, 1979, now U.S.Pat. No. 4,289,782, which was a division of Ser. No. 30,782 filed Apr.17, 1979, now U.S. Pat. No. 4,230,868, which was a division of Ser. No.883,113 filed Mar. 3, 1978, now U.S. Pat. No. 4,174,454, which was adivision of Ser. No. 750,991 filed Dec. 15, 1976, now U.S. Pat. No.4,118,742, which was a CIP of Ser. No. 608,415 filed Aug. 28, 1975, nowabandoned.

BACKGROUND OF THE INVENTION

The incidence of viral upper respiratory disease is immense. It has beenestimated that nearly a billion cases annually appear in the UnitedStates alone. Studies performed in England (Tyrell and Bynoe, 1966)indicated that 74 percent of persons having colds were infected withrhinoviruses. Because more than 80 strains of rhinoviruses are alreadyidentified, the development of a practical rhinovirus vaccine is notfeasible, and chemotherapy appears to be the more desirable approach.

The ability of chemical compounds to suppress the growth of viruses invitro is readily demonstrated by using a virus plaque suppression testsimilar to that described by Siminoff, Applied Microbiology, 9(1),66(1961).

Certain antifungal 1-dimethylaminosulfonyl-2-aminobenzimidazolecompounds have been disclosed in U.S. Pat. No. 3,853,908.

It is the purpose of this invention to provide novel benzimidazolecompounds which inhibit the growth of viruses, particularlyrhinoviruses, polio viruses, Coxsackie viruses, echo virus, and Mengovirus.

SUMMARY OF THE INVENTION

This invention concerns pharmacologically useful sulfonyl benzimidazolecompounds having the formula ##STR1## wherein

R₁ is C₁ -C₅ alkyl, C₃ -C₇ cycloalkyl, phenyl, furyl, thienyl,thiazol-2-yl, 2-acetamido-4-methylthiazol-5-yl, 1,3,4-thiadiazol-2-yl,2-methyl-1,3,4-thiadiazol-5-yl, 2-methylamino-1,3,4-thiadiazol-5-yl orR₄ R₅ N--, wherein R₄ and R₅ are independently C₁ -C₃ alkyl or R₄ andR₅, when taken together with the nitrogen atom to which they areattached, are pyrrolidino, piperidino or morpholino;

R₂ is amino, formamido, acetamido, propionamido or butyramido;

R₃ is hydroxy, C₂ -C₈ alkanoyloxy, phenylacetoxy, α-C₁ -C₇alkyl-α-hydroxybenzyl or benzoyloxy; or 1,3-dithiolan-2-yl,1,3-dithian-2-yl, tetrazol-5-yl, 1-(C₁ -C₄ alkyl)tetrazol-5-yl,1,3,4-oxadiazol-2-yl, or 2-(C₁ -C₄ alkyl)oxadiazol-5-yl; or ##STR2##wherein R₆ is hydrogen, C₁ -C₇ alkyl, C₃ -C₇ cycloalkyl, (C₃ -C₇cycloalkyl)methyl, 1-(C₃ -C₇ cycloalkyl)ethyl, benzyl, phenyl or phenylsubstituted by C₁ -C₄ alkyl, C₁ -C₄ alkoxy, chloro, bromo, iodo, nitroor trifluoromethyl; or Z═C(R₆)--, wherein Z is hydroxyimino, C₁ -C₄alkoxyimino, C₁ -C₄ acyloxyimino, benzyloxyimino, benzoyloxyimino,hydrazono, thiocarbamylhydrazono, carboxymethoxyimino,methoxycarbonylhydrazono, ethoxycarbonylhydrazono, carbamylhydrazono, C₁-C₄ alkoxycarbonylethylcarbonyloxyimino,benzyloxycarbonylaminomethylcarbonyloxyimino,p-nitrobenzyloxycarbonylethylcarbonyloxyimino,phthalimidomethylcarbonyloxyimino,2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxyimino orC₁ -C₇ alkylidene; and

R₃ is at the 5 or 6 position.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENT

The present invention relates to new organic sulfonyl compounds that areuseful as antiviral agents and to methods for their production. Thecompounds of the invention are prepared by reacting a tautomericbenzimidazole compound of the formula ##STR3## with a sulfonyl chloridecompound having the formula

    R.sub.1 SO.sub.2 Cl

wherein R₁ and R₃ are as defined hereinabove, and R₂ is amino.

A preferred group of compounds are the compounds of formula (I) wherein

R₁ is C₁ -C₄ alkyl, C₅ -C₇ cycloalkyl, thienyl, phenyl or R₄ R₅ N-wherein R₄ and R₅ are independently C₁ -C₃ alkyl;

R₂ is defined as before;

R₃ is 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, 1-(C₁ -C₃alkyl)tetrazole-5-yl, 1,3,4-oxadiazol-2-yl, α-C₁ -C₇alkyl-α-hydroxybenzyl; or ##STR4## wherein R₆ is hydrogen, C₁ -C₄ alkyl,phenyl, or phenyl substituted by chloro, bromo, or iodo; or Z═C(R₆)--,wherein Z is hydroxyimino, C₁ -C₄ alkoxyimino, C₁ -C₄ acyloxyimino,benzyloxyimino, benzoyloxyimino, hydrazono, thiocarbamylhydrazono,carboxymethoxyimino, methoxycarbonylhydrazono, ethoxycarbonylhydrazono,carbamylhydrazono, C₁ -C₄ alkoxycarbonylethylcarbonyloxyimino,benzyloxycarbonylaminomethylcarbonyloxyimino,p-nitrobenzyloxycarbonylethylcarbonyloxyimino,phthalimidomethylcarbonyloxyimino,2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxyimino, orC₁ -C₇ alkylidene; and

R₃ is at the 5 or 6 position.

Another preferred group of compounds are the compounds of formula (I)wherein

R₁ is defined as before;

R₂ is amino, formamido, acetaido, or propionamido;

R₃ is hydroxy, C₂ -C₈ alkanoyloxy, phenylacetoxy, or benzoyloxy; or1,3-dithiolan-2-yl, 1,3-dithian-2-yl, tetrazol-5-yl, 1-(C₁ -C₄alkyl)tetrazol-5-yl, 1,3,4-oxadiazol-2-yl, or 2-(C₁ -C₄alkyl)oxadiazol-5-yl; or ##STR5## wherein R₆ is defined as before; orZ═C(R₆)-- wherein Z is hydroxyimino, C₁ -C₄ alkoxyimino, hydrazono,thiocarbamylhydrazono, or carbamylhydrazono; and

R₃ is at the 5 or 6 position.

The term "tautomeric benzimidazole" refers to a benzimidazole reagentwhich can be substituted at either nitrogen atom with a hydrogen atom.The benzimidazole reactant, unsubstituted on nitrogen and bearing asubstituent group at the 5 position of the benzene moiety, has acorresponding tautomeric form wherein the substituent residesalternatively at the 6 position. The isomer mixture can be indicated bynumbering the alternate positions as 5(6). As a consequence of suchtautomerism, the reaction of a 5(6)-substituted benzimidazole with asulfonyl chloride produces isomeric mixtures of 5(6)-substitutedsulfonylbenzimidazoles.

The following definitions refer to the various terms used throughoutthis disclosure. The term "furan" refers to the furan radical attachedat the 2 or 3 position. The term "thienyl" refers to the thiopheneradical attached at the 2 or 3 position. The term "thiazol-2-yl" or"2-thiazole" refers to the thiazole radical attached at the 2 position.The term "1,3,4-thiadiazole-2-yl" or "thiadiazol-2-yl" refers to the1,3,4-thiadiazole radical attached at the 2 position. The term"2-methyl-1,3,4-thiadiazol-5-yl" or"2-methylamino-1,3,4-thiadiazol-5-yl" refers to a2-substituted-1,3,4-thiadiazole radical attached at the 5 position. Theterm "1,3-dithiolan-2-yl" refers to the 1,3-dithiolane radical attachedat the 2 position. The term "1,3-dithian-2-yl" refers to the1,3-dithiane radical attached at the 2 position. The term "1-(C₁ - C₄alkyl)tetrazol-5-yl" refers to a 1-methyl-, 1-ethyl-, 1-propyl, or1-butyltetrazole radical attached at the 5 position. The term "2-(C₁ -C₄alkyl)oxadiazol-5-yl" refers to a 2-methyl-, 2-ethyl-, 2-propyl-, or2-butyl-1,3,4-oxadiazole radical attached at the 5 position. The term"1,3,4-oxadiazol-2-yl" refers to the 1,3,4-oxadiazole radical attachedat the 2-position.

The term "C₁ -C₈ alkyl" refers to the straight and branched aliphaticradicals of one to eight carbon atoms including methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl,sec-amyl, sec-isoamyl (1,2-dimethylpropyl), tert-amyl(1,1-dimethylpropyl), hexyl, isohexyl (4-methylpentyl), sec-hexyl(1-methylpentyl), 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl,isoheptyl (5-methylhexyl), sec-heptyl (1-methylhexyl),1-ethyl-2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl,1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl,1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl,isooctyl (6-methylheptyl), sec-octyl(1-methylheptyl),tert-octyl(1,1,3,3-tetramethylbutyl and the like. The term C₁ -C₈ alkylincludes within its definition the terms "C₁ -C₃ alkyl", "C₁ -C₄ alkyl,""C₁ -C₅ alkyl," and "C₁ -C₇ alkyl."

The term "C₁ -C₈ alkyl carbinol" refers to the straight and branchedaliphatic alcohols of one to eight carbon atoms as exemplified in theterm "C₁ -C₈ alkyl."

The term "C₃ -C₇ cycloalkyl" refers to the saturated alicyclic rings ofthree to seven carbon atoms such as cyclopropyl, methylcyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 1-, 2-, 3- or 4-methylcyclohexyland cycloheptyl. The term "(C₃ -C₇ cycloalkyl)methyl" refers to a methylradical substituted with saturated alicyclic rings of three to sevencarbon atoms as exemplified in the term "C₃ -C₇ cycloalkyl", such ascyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl and the like. The term "1-(C₃ -C₇cycloalkyl)ethyl" refers to ethyl radicals substituted on the carbonatom in the 1 position with saturated alicyclic rings of three to sevencarbon atoms. The term "C₃ -C₇ cycloalkylacetic acid" refers to aceticacid substituted on the carbon atom in the 2 position with saturatedalicyclic rings of three to seven carbon atoms such ascyclopropaneacetic acid, cyclopentane acetic acid and the like. The term"2-(C₃ -C₇ cycloalkyl)propionic acid" refers to propionic acidsubstituted on the carbon atom in the 2 position with saturatedalicyclic rings of three to seven carbon atoms such as2-(cyclopropane)propionic cid, 2-(cyclohexane)propionic acid and thelike.

The term "C₂ -C₈ alkanoyl" refers to the straight chain aliphatic acylradicals of two to eight carbon atoms and the branched aliphatic acylradicals of four to five carbon atoms such as acetyl, propionyl,butyryl, 2-methylpropionyl, pentanoyl, hexanoyl, heptanoyl, octanoyl,and the like.

The term "C₁ -C₇ alkylidene" refers to straight and branched radicals ofone to seven carbon atoms such as methylene, ethylidene, propylidene,isopropylidene, butylidene, isobutylidene, 3-methyl-2-butylidene,n-hexylidene and the like.

The term "C₁ -C₄ alkoxy" includes the straight and branched aliphaticether radicals of one to four carbon atoms such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and the like. Theterm "C₁ -C₄ alkylamino" refers to the aliphatic primary and secondaryamine radical of one to four carbon atoms derived from methylamine,ethylamine, propylamine, isopropylamine, butylamine, sec-butylamine,dimethylamine, methylethylamine, diethylamine, methylpropylamine and thelike. The term "C₁ -C₄ alkoxyamine" refers to the O-aliphatichydroxylamine radical of one to four carbon atoms derived fromhydroxylamine. Methoxyamine hydrochloride is available from commercialsources. Other hydroxylamine derivatives are available by (A) alkylationof acetone oxime by C₁ -C₄ alkyl halides followed by acid hydrolysis,(B) alkylation of N-hydroxyphthalimide followed by hydrazinolysis or (C)alkylation of benzohydroxamic acid followed by acid hydrolysis.

The preferred reactants are benzimidazole compounds bearing5(6)-substituents which will not react with the sulfonyl chloridereactant under the reaction conditions. The benzimidazole compound andthe sulfonyl chloride are normally employed in approximately equimolarquantities, although an excess of either can be used if desired. Thereaction can be carried out in any number of unreactive solvents,including acetone, tetrahydrofuran (THF), tertiary amides such asN,N-dimethylformamide (DMF), and chlorinated hydrocarbons such asdichloromethane, dichloroethane and chloroform. The reaction medium mayalso contain added base to serve as an acid-binding agent. Some examplesof suitable bases for this purpose are pyridine, triethylamine,N-methylmorpholine, sodium bicarbonate, and sodium hydride. A preferredsolvent medium for the reaction is acetone containing triethylamine ortetrahydrofuran with DMF containing sodium hydride as a base.

The reaction is best carried out at a temperature between roomtemperature and the reflux temperature of the solvent system empolyed.Preferably, the reaction is carried out at reflux temperature, and atthis temperature, the reaction is substantially complete within 1 to 48hours.

The product of the reaction is a 1-sulfonylbenzimidazole compound,hereinafter called the sulfonylbenzimidazole compound. The product maybe isolated by filtering the reaction mixture and concentrating thefiltrate to induce crystallization. Alternatively, the reaction mixturecan be evaporated to dryness and the residue treated with a suitablesolvent such as acetone or methanol to separate and remove any insolublematerial. The solution containing the sulfonylbenzimidazole compound isconcentrated to crystallize the product or it is evaporated to give asecond residue, which is dissolved in methanol for example. Thesulfonylbenzimidazole compound is recovered from the methanol bycrystallization.

The reaction of the tautomeric benzimidazole compound and the sulfonylchloride generally provides a 1:1 mixture of 5- and 6-substitutedsulfonylbenzimidazole isomers. The isomers are separable by fractionalcrystallization or by column chromatography. Usually the 6-isomercrystallizes first from a solution of the mixture. For example, whenethyl 2-amino-5-benzimidazolecarboxylate is reacted withdimethylsulfamoyl chloride in acetone containing triethylamine, ethyl1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate crystallizesfirst from the reaction mixture. The acetone mother liquors containpredominantly ethyl1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxylate and residualamounts of the 6-isomer. The isomers can be identified by their nuclearmagnetic resonance spectra in the phenyl proton region (7.0 to 8.3 ppm).

Some of the compounds of the invention can be prepared by performingchemical operations such as acylation, oxidation or reduction on theappropriate sulfonylbenzimidazole precursor. When the reactions areperformed on a precursor which is an isomeric mixture ofsulfonylbenzimidazoles, the isomeric products can be separated bymethods such as fractional crystallization or chromatography.

It will be appreciated that advantageous chemical reactions can beperformed at optional stages of product synthesis. The benzimidazolereactant can be chemically modified and then reacted with theappropriate sulfonyl chloride to provide the sulfonylbenzimidazoleproduct. Alternatively, a sulfonylbenzimidazole intermediate can beprepared and then chemically modified to provide the final product.Suitable benzimidazole reactants are those having substituent groupswhich can be converted to the desired 5(6)-substituents either prior toor after reaction with the appropriate sulfonyl chloride. The ethylesters of 2-substituted-5(6)-benzimidazolecarboxylic acids areespecially suitable reactants because the ester function can be reactedto provide other intermediate compounds which can be converted to finalproducts as described hereinafter.

The ethyl esters of the sulfonylbenzimidazolecarboxylic acidintermediates or isomeric mixtures thereof can be reacted with hydrazinein a carbinol solvent to yield the corresponding hydrazides. Forexample, ethyl1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate can berefluxed with hydrazine hydrate in methanol to provide1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide. The hydrazide compounds can be converted to the corresponding5(6)-[(2-substituted)oxadiazol-5-yl]sulfonylbenzimidazoles by heating atelevated temperatures with ortho esters such as ethyl orthoformate,ethyl orthoacetate or ethyl orthopropionate as illustrated in reactionscheme I. For example when1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazole carboxylic acidhydrazide is refluxed with ethyl orthoacetate the product is1-dimethylaminosulfonyl-2-acetamido-5(6)-(2-methyloxadiazol-5-yl)benzimidazole.

The ethyl esters of the1-sulfonyl-2-substituted-5(6)-benzimidazolecarboxylic acids can bereduced chemically to provide the corresponding hydroxymethylintermediates. For example, ethyl1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate can bereduced with sodium bis(2-methoxyethoxy)-aluminum hydride intetrahydrofuran to provide1-dimethylaminosulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole. Abetter method reacts the sulfonyl chloride, R₁ SO₂ Cl, with theappropriate 2-substituted-5(6)-hydroxymethylbenzimidazole. The required5(6)-hydroxymethylbenzimidazole reactant can be prepared from thecorresponding ethyl 2-substituted-5(6)-benzimidazolecarboxylic acid byreduction with sodium bis(2-methoxyethoxy)aluminum hydride in an aproticsolvent as described above. The preferred method for preparing largequantitites of the hydroxymethyl sulfonyl benzimidazole intermediatesbegins with 4-chloro-3-nitrobenzyl alcohol. The benzyl alcohol isammoniated to give 4-amino-3-nitrobenzyl alcohol. The nitro alcohol ishydrogenated catalytically to yield 4-hydroxymethyl-o-phenylenediamine.The phenylenediamine is ring closed to provide the desired2-substituted- 5(6)-hydroxymethylbenzimidazole intermediate by methodsknown to the benzimidazole art.

Generally, the 5(6)-hydroxymethyl sulfonylbenzimidazole compounds areimportant as intermediates which can be converted to the corresponding5(6)-formyl derivatives. The oxidation of the hydroxymethyl carbinolfunction to provide a carboxaldehyde compound with virus inhibitingproperties is certainly unexpected. Furthermore the conversion of thecarboxaldehyde function to a carbon-nitrogen double bond function insuch a compound increases the antiviral activity to a considerabledegree.

The sulfonylbenzimidazole carboxaldehyde compounds wherein R₆ ishydrogen can be prepared from the corresponding1-sulfonyl-2-substituted-5(6)-hydroxymethylbenzimidazole compounds byoxidation of the hydroxymethyl group with Jones reagent, a solution ofchromic acid and sulfuric acid in water. For example,1-dimethylaminosulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole yields1-dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole after oxidationwith Jones reagent. The sulfonylbenzimidazole carboxaldehyde compoundscan be converted to their 5(6)-hydrazonomethylene,5(6)-carbamylhydrazonomethylene, 5(6)-thiocarbamylhydrazonomethylene,5(6)-hydroxyiminomethylene or 5(6)-(C₁ -C₄)alkyloxyiminomethylenederivatives by reacting them with hydrazine, semicarbazide,thiosemicarbazide, hydroxylamine, or C₁ -C₄ alkoxyamines in the usualmanner since the carboxaldehyde function is quite reactive. The5(6)-(1,3-dithiolan-2-yl) and 5(6)-(1,3-dithan-2-yl) derivatives can beobtained by reacting the 5(6)-formyl sulfonylbenzimidazole compoundswith 1,2-ethanedithiol or 1,3-propanedithiol respectively in thepresence of boron trifluoride etherate and recovering the cyclicthioacetal products.

When the oxime and oxime derivatives are prepared, the products areusually mixtures of the syn and anti isomers. The proportion of the antiisomer can be increased by conventional methods, e.g. fractionalcrystallization or high pressure chromatography. As the anti isomer ismore active biologically this enrichment process is useful. Thesecarbonyl reactions are illustrated in Reaction Scheme I. ##STR6##

The 5(6)-keto sulfonylbenzimidazole compounds wherein R₃ is R₆ CO can beprepared from the corresponding 5(6)-keto benzimidazoles by reactionwith the sulfonyl chloride, R₁ SO₂ Cl. The keto benzimidazole reactantcan be prepared from the appropriate keto o-phenylenediamine by methodsknown to the benzimidazole art. Belgian published application No. 93791discloses the preparation of keto o-phenylenediamines of the formula##STR7## wherein R₆ is lower alkyl, cycloalkyl, phenyl or phenylsubstituted by halogen, lower alkyl or lower alkoxy. The method ofpreparation involves the ammonolysis and reduction of a4-halo-3-nitrophenyl ketone which is prepared by the Friedel-Craftsreaction of either (1) a 4-halo-3-nitrobenzoyl chloride with anappropriate hydrocarbon or (2) a halobenzene with an appropriate acidchloride followed by aromatic nitration. Such methods make available therequired keto o-phenylenediamines wherein R₆ in the formula above isadditionally C₃ -C₇ cycloalkyl, (C₃ -C₇ cycloalkyl)methyl, 1-(C₃ -C₇cycloalkyl)ethyl or benzyl. Alternatively the keto benzimidazolereactants can be prepared from acetanilide by a Friedel-Crafts acylationwith the appropriate derivative of a C₂ -C₈ alkanoic acid, C₃ -C₇cycloalkyl carboxylic acid, C₃ -C₇ cycloalkylacetic acid, 2-(C₃ -C₇cycloalkyl)propionic acid, phenylacetic acid, benzoic acid orsubstituted benzoic acid. The resulting 4-keto acetanilide is nitratedto give a 2-nitro-4-ketoacetanilide. The acetanilide is hydrolyzed togive a 2-nitro-4-ketoaniline. The nitroaniline is catalyticallyhydrogenated to yield a 4-keto-o-phenylenediamine which is ring closedto provide the appropriate 2-substituted-5(6)-ketobenzimidazole. Thefollowing embodiment illustrates in principle the preparation of a5(6)-keto sulfonylbenzimidazole compound. 4-Propionylacetanilide isnitrated at 0° C. to yield 2-nitro-4-propionylacetanilide. Theacetanilide is hydrolyzed and catalytically hydrogenated to give4-propionyl-o-phenylenediamine. The phenylenediamine is reacted withcyanogen bromide to give 2-amino-5(6)-propionylbenzimidazole. Thepropionylbenzimidazole is reacted with dimethylsulfamoyl chloride toprovide 1-dimethylaminosulfonyl-2-amino-5(6)-propionylbenzimidazole.These methods make available the 5(6)-(C₂ -C₈)alkanoyl, 5(6)-(C₃-C₇)cycloalkylcarbonyl, 5(6)-(C₃ -C₇)cycloalkylacetyl, 5(6)-[2-(C₃ -C₇cycloalkyl) propionyl], 5(6)-phenylacetyl, 5(6)-benzoyl or the5(6)-substituted-benzoyl sulfonylbenzimidazole compounds. The 5(6)-ketosulfonylbenzimidazole compounds are represented by the formula ##STR8##wherein R₆ is C₁ -C₇ alkyl, C₃ -C₇ cycloalkyl, (C₃ -C₇cycloalkyl)methyl, 1-(C₃ -C₇ cycloalkyl)ethyl, benzyl, phenyl or phenylsubstituted by C₁ -C₄ alkyl, C₁ -C₄ alkoxy, chloro, bromo, iodo, nitroor trifluoromethyl, and R₁ and R₂ are as defined previously. As with thesulfonylbenzimidazole carboxaldehyde compounds, the 5(6)-ketosulfonylbenzimidazole compounds can be reacted with hydrazine,semicarbazide, thiosemicarbazide, hydroxylamine or C₁ -C₄ alkoxyaminesto provide their hydrazone, semicarbazone, thiosemicarbazone, oxime, orC₁ -C₄ alkoxyamine derivatives.

The compounds of formula I wherein R₃ is Z═C(R₆)-- wherein Z is anacyloxyamine are prepared by reacting the correspondinghydroxyiminobenzimidazole with the appropriate acylating agent (such asan anhydride).

The compounds of formula I wherein R₃ is Z═C(R₆)-- wherein Z is analkoxyamine are prepared by reacting the appropriate ketobenzimidazolewith an alkoxyamine, or by alkylating the correspondinghydroxyiminobenzimidazole (suitable alkylating agents are an alkalimetal alkoxide and alkyl halide). The benzyloxyamines are prepared in acorresponding manner.

The compounds of formula I wherein R₃ is Z═C(R₆)-- wherein z is C₁ -C₄alkoxycarbonylethylcarbonyloxyamine are prepared by reacting theappropriate hydroxyiminobenzimidazole with a carboalkoxypropionylhalide.

The compounds of formula I wherein R₃ is Z═C(R₆)-- wherein Z isp-nitrobenzyloxycarbonylethylcarbonyloxyamine are prepared by reactingthe appropriate hydroxyiminobenzimidazole withp-nitrobenzyloxycarbonylpropionyl halide. Succinic anhydride andp-nitrobenzyl alcohol in dimethylformamide and reflux provides thep-nitrobenzyloxycarbonylpropionic acid, followed by making the acidchloride using oxalyl chloride and pyridine.

The compounds of formula I wherein R₃ is Z═C(R₆)-- wherein Z isbenzyloxycarbonylaminomethylcarbonyloxyamine are prepared by reactingthe appropriate hydroxyiminobenzimidazole withbenzyloxycarbonylaminomethylcarboxylic acid chloride.

The compounds of formula I wherein R₃ is Z═C(R₆)-- wherein Z isphthalimidomethylcarbonyloxyamine are prepared by reacting theappropriate hydroxyiminobenzimidazole with phthalimidomethylcarboxylicacid chloride.

The compounds of formula I wherein R₃ is Z═C(R₆)-- wherein Z is2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxyamine areprepared by reacting the appropriate hydroxyiminobenzimidazole with3-(3-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)propionic acid chloride.The preparation of3-(3-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)propionic acid isdiscussed by Masumi Itoh, Chem. Pharm. Bull. 17 (8) 1679-1686 (1969).

However the keto carbonyl function is less reactive than thecarboxaldehyde function. The keto function can be activated byprotonating the sulfonylbenzimidazole compound under acidic conditionsand subsequently carbon-nitrogen double bond formation occurs readily.These nitrogen derivatives are represented by the formula ##STR9##wherein R₇ is hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ acyloxy, benzyloxy,benzoyloxy, amino, thiocarbamylamino, carboxymethoxy,methoxycarbonylamine, ethyloxycarbonylamino, carbamylamino, C₁ -C₄alkoxycarbonylethylcarbonyloxy, benzyloxycarbonylaminomethylcarbonyloxy,p-nitrobenzyloxycarbonylethylcarbonyloxy, phthalimidomethylcarbonyloxy,2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxy, and R₁,R₂, and R₆ are as defined previously. When R₆ is hydrogen, the nitrogenderivatives are those of the 5(6)-formyl sulfonylbenzimidazolecompounds.

The nitrogen functions are named according to the carbonyl reagent fromwhich they are derived as follows:

    ______________________________________                                        carbonyl reagent  N-function (name)                                           ______________________________________                                        hydroxylamine     hydroxyimino                                                methoxyamine      methoxyimino                                                ethoxyamine       ethoxyimino                                                 propoxyamine      propoxyimino                                                buytoxyamine      butoxyimino                                                 hydrazine         hydrazono                                                   semicarbazide     carbamylhydrazono                                           thiosemicarbazide thiocarbamylhydrazono                                       acyloxyamine      acyloxyimino                                                benzyloxyamine    benzyloxyimino                                              benzoyloxyamine   benzoyloxyimino                                             carboxymethoxyamine                                                                             carboxymethoxyimino                                         methoxycarbonyl-  methoxycarbonyl-                                            hydrazine         hydrazono                                                   ______________________________________                                    

The C₁ -C₇ alkylidene derivatives are prepared from the corresponding(α-hydroxy-α-C₁ -C₇ alkyl)benzyl derivatives by dehydration withp-toluenesulfonic acid.

The (α-hydroxy-α-C₁ -C₇ alkyl)benzyl derivatives and the (α-hydroxy-α-C₁-C₇ branched alkyl)benzyl derivatives are prepared by reacting thecorresponding keto derivative with the appropriate Grignard reagentfollowed by hydrolysis.

The sulfonylbenzimidazole compounds wherein R₃ is a heterocyclic moietysuch as 1,3-dithiane, 1,3-dithiolane, oxadiazole or tetrazole can beprepared by the following methods. The following embodiment illustratesin principle the preparation of the 5(6)-(1-alkyltetrazol-5-yl)sulfonylbenzimidazole compounds of the invention. The process begins bypreparing the desired2-substituted-5(6)-(1-alkyltetrazol-5-yl)benzimidazole reactant asillustrated by the following example. 4-Aminobenzonitrile is acetylatedand nitrated to give 3-nitro-4-acetamidobenzonitrile. The benzonitrileis reacted with sodium azide in dimethylformamide in the presence ofammonium chloride to yield 5-(3-nitro-4-acetamidophenyl)tetrazole. Thetetrazole moiety is alkylated with methyl iodide in acetone andtriethylamine to provide1(2)-methyl-5-(3-nitro-4-acetamidophenyl)tetrazole as an isomericmixture. The tetrazole mixture is hydrolyzed with concentrated sulfuricacid at room temperature for several hours to yield1(2)-methyl-5-(3-nitro-4-aminophenyl)tetrazole. The nitro group of thebenzene moiety is hydrogenated in ethanol-ethyl acetate at 30° C. in thepresence of palladium-on-carbon to give1(2)-methyl-5-(3,4-diaminophenyl)tetrazole. The diaminophenyltetrazoleis reacted with cyanogen bromide in methanol-water to yield essentiallyone methyl isomer, 2-amino-5(6)-(1-methyltetrazol-5-yl)benzimidazole.When the benzimidazole is reacted with dimethylsulfamoyl chloride inacetone in the presence of triethylamine, the product is1-dimethylaminosulfonyl-2-amino-5(6)-(1-methyltetrazol-5-yl)benzimidazole.By employing the appropriate2-substituted-5(6)-(1-alkyltetrazol-5-yl)benzimidazole reactants andsulfonyl chlorides as described above, other5(6)-(1-alkyltetrazol-5-yl)sulfonylbenzimidole compounds of theinvention can be prepared.

The 5(6)-(tetrazol-5-yl)sulfonylbenzimidazale compounds are useful forpreparing the corresponding 5(6)-(oxadiazol-5-yl)sulfonylbenzimidazolecompounds by thermal rearrangement. In the preparation of the tetrazolecompounds, 5-(3-nitro-4-acetamidophenyl)tetrazole is acylated to yield a1(2)-acyl-5-(3-nitro-4-acetamidophenyl)tetrazole. The ultimate productfrom such a reactant is a5(6)-[1(2)-acyltetrazol-5-yl]sulfonylbenzimidazole compound which uponthermolysis at elevated temperatures yields the corresponding5(6)-(2-substituted-oxadiazol-5-yl)sulfonylbenzimidazole compounds.

The sulfonylbenzimidazole compounds wherein R₃ is hydroxy can beprepared from the corresponding 5(6)-hydroxybenzimidazole reactants. Thepreparation of the required hydroxybenzimidazole compounds begins withthe reduction of 4-methoxy-2-nitroaniline to the corresponding4-methoxy-o-phenylenediamine. The phenylenediamine is ring closed toprovide a 2-substituted-5(6)-methoybenzimidazole by methods known to thebenzimidazole art. The methyl ether is cleaved with hydrobromic acid togive a 2-substituted-5(6)-hydroxybenzimidazole. The hydroxybenzimidazoleis reacted with the appropriate sulfonyl chloride to provide therequired 2-substituted-5(6)-hydroxy sulfonylbenzimidazole compounds.

The phenolic hydroxyl function of the 5(6)-hydroy sulfonylbenzimidazolecompounds can be reacted with the anhydrides or chlorides of C₂ -C₈alkanoic acids, phenylacetic acid or benzoic acid in an aprotic solventto provide the corresponding esters. The ester products derived from the5(6)-hydroxy sulfonylbenzimidazole reactants are respectively the5(6)-(C₂ -C₈)alkanoyloxy, 5(6)-phenylacetoxy or 5(6)-benzoyloxysulfonylbenzimidazole compounds. Alternatively the hydroxysulfonylbenzimidazole compounds can be esterified with the appropriateacid reactant in the presence of 1,1'-carbonyldiimidazole indimethylformamide.

The benzimidazole compounds which are required as starting materials inthe foregoing process can be prepared according to a variety of methodsknown to the benzimidazole art. The preparation of a variety ofbenzimidazoles is well documented in Weissberger's The Chemistry ofHeterocyclic Compounds, Imidazole and Its Derivatives, IntersciencePublishers Co., New York., 1953. The 2-aminobenzimidazole reactants canbe prepared by cyclizing the appropriate o-phenylenediamines withcyanogen bromide as described by Buttle, et al., Bio. Chem. J. 32, 1101(1938) and British Pat. No. 551,524. Acylation of the2-aminobenzimidazole reactant with acetic or propionic anhydrideprovides the 2-acetamido-or 2-propionamidobenzimidazoles. The2-formamidobenzimidazole reagents can be obtained by reacting theappropriate 2-aminobenzimidazole with the mixed anhydride obtained fromformic acid and acetic anhydride. Alternatively, the 2-acylaminosulfonylbenzimidazole compounds can be prepared from the corresponding2-amino sulfonylbenzimidazole compounds by acylation as describedhereinabove. Ethyl 2-amino-5(6)benzimidazolecarboxylate is described byPaget, et al., J. Med. Chem. 12, 1010 (1969). Illustrative of suchbenzimidazole compounds which can be reacted with the appropriatesulfonyl chlorides are the 2-amino-, 2-formamido, 2-acetamido- or2-propionamido-benzimidazoles substituted in the 5(6) position withhydroxy, hydroxymethyl, ethoxycarbonyl, formyl, keto, and the like.

Among the sulfonyl chloride compounds which are required as reactants,methanesulfonyl chloride (mesylchloride), isopropylsulfonyl chloride,dimethylsulfamoyl chloride, benzenesulfonyl chloride,2-thiophenesulfonyl chloride, and2-acetamido-4-methyl-5-thiazolesulfonyl chloride are commerciallyavailable. The preparation of 3-thiophenesulfonyl chloride and 2(or3)-furansulfonyl chloride is described By Arcoria et al., J. Org. Chem.,39, 1689 and 3595 (1974). 2-Thiazolesulfonyl chloride,2-thiadiazolesulfonyl chloride, 2-methyl-5-thiadiazolesulfonyl chlorideand 2-methylamino-5-thiadiazolesulfonyl chloride are available from2-thiazolethiol, 2-thiadiazolethiol, 2-methyl-5-thiadiazolethiol and2-methylamino-5-thiadiazolethiol respectively by oxidation of the thiolfunction with bromine or chlorine in aqueous solution. Other C₁ -C₅alkyl and C₃ -C₇ cycloalkyl sulfonyl chlorides can be prepared by thechlorination of the appropriate alkyl thiol or by reacting sulfurylchloride with sodium alkyl sulfonates derived from the correspondingcarbinols and sulfuric acid. The N,N-dialkylsulfamoyl chlorides can beprepared as described by Bindely et al., J. Am. Chem. Soc. 61, 3250(1939), by reacting a secondary amine salt with sulfuryl chloride.Alternatively, they can be prepared by reacting a chloramine compound ofthe formula

    R.sub.4 R.sub.5 N--Cl

with a sulfur dioxide at a temperature of -5° to 30° C. The chloraminecompounds are prepared by reacting the corresponding secondary amineswith antimony pentachloride, sodium hypochlorite or sulfuryl chloride.

Further illustrative of the sulfonyl chlorides which can be reacted withthe benzimidazole compounds are ethyl-, propyl-, isopropyl, butyl-,isobutyl-, sec-butyl, tert-butyl, amyl-, isoamyl-, sec-isoamyl-, andtert-amylsulfonyl chloride in addition to cyclobutyl-, cyclopentyl-,cyclohexyl-, and cycloheptylsulfonylchloride.

Other sulfamoyl chlorides which can be employed are diethyl-, dipropyl-,N-methyl-N-ethyl-, N-methyl-N-propyl-, N-ethyl-N-propyl-,N-methyl-N-isopropyl-, N-ethyl-N-isopropyl, N-propyl-N-isopropyl-,diisopropyl-, pyrrolidino-, piperidino-, and morpholinosulfamoylchloride.

For consistency in nomenclature, the sulfonylbenzimidazole compoundswill be named as sulfonyl derivatives. For example, the product of thereaction of dimethylsulfamoyl chloride and ethyl2-amino-5-benzimidazolecarboxylate is named ethyl1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate ratherthan ethyl 1-dimethylsulfamoyl-2-amino-5(6)-benzimidazolecarboxylate.The compounds of the invention were tested by the following methods.

TEST METHODS

African green monkey kidney cells (BSC-1) or Hela cells (5-3) were grownin 25 cc. Falcon flasks at 37° C. in medium 199 with 5 percentinactivated fetal bovine serum (FBS), penicillin (150 units 1 ml.) andstreptomycin (150 mcg./ml.). When confluent monolayers were formed, thesupernatant growth medium was removed and 0.3 ml. of an appropriatedilution of virus (echo, Mengo, Coxsackie, polio or rhinovirus) wasadded to each flask. After absorption for one hour at room temperature,the virus infected cell sheet was overlaid with a medium comprising onepart of 1 percent Ionagar No. 2 and one part double strength medium 199with FBS, penicillin, and streptomycin which contains drug atconcentrations of 100, 50, 25, 12, 6, 3 and 0 micrograms per milliliter(mcg./ml.). The flask containing no drug served as the control for thetest. The stock solutions of sulfonylbenzimidazole compounds were madeup in dimethylsulfoxide dilution at a concentration of 10⁴ mcg./ml. Theflasks were incubated for 72 hours at 37° C. for polio, Coxsackie, echo,and Mengo virus and 120 hours at 32° C. for rhinovirus. Plaques wereseen in those areas where the virus infected and reproduced in thecells. A solution of 10 percent formalin and 2 percent sodium acetatewas added to each flask to inactivate the virus and fix the cell sheetto the surface of the flask. The virus plaques, irrespective of size,were counted after staining the surrounding cell areas with crystalviolet. The plaque count was compared to the control count at each drugconcentration. The activity of the test compound was expressed aspercentage plaque reduction, or percent inhibition. Alternatively, thedrug concentration which inhibits plaque formation by 50 percent can beused as a measure of activity. The 50 percent inhibition is indicated bythe symbol I₅₀.

Test results are expressed in terms of Polio virus type I inhibitionbecause the virus is easy to grow and consistent test results areobtained. However, the activity of the preferred compounds was confirmedagainst other virus cultures such as Coxsackie (A9, A21, B5), echovirus(strains 1-4), Mengo, rhinovirus (25 strains) and Polio (type I, II,III). Test results for various sulfonylbenzimidazole compounds aresummarized in Table I below where column 1 gives the Example number fromthe previous chemical examples, column 2 gives the 5(6)-position of thecorresponding benzimidazole product, and columns 3-10 indicate thepercentage virus plaque reduction at drug dilutions from 0.75-100micrograms per milliliter (mcg./ml.).

                                      TABLE I                                     __________________________________________________________________________    Polio I Plaque Reduction of l-Substituted-                                    sulfonyl-2-amino-5(6)-Substituted-Benzimidazoles                                         Drug Concentration (mcg./ml.)*                                     Example No.                                                                          Isomer                                                                            100 50  25  12  6   3   1.5 0.75                                   __________________________________________________________________________    13     5(6)                                                                              100  95  54  0  0   0   0   0   Percent                            14     5(6)                                                                              100 100 100 100 100 100 81  15  Plaque                             15     5(6)                                                                              Toxic                                                                              97  87  59 37  24  0   0   Reduction                          16     5(6)                                                                              100 100 100 100 99  83  47  25                                     29     6   Toxic                                                                             100 100 100 100 100 100 100                                    18     5(6)                                                                              100 100 100 100 100 99  54  27                                     18     6   100 100 100 100 100 100 76  41                                     19     5(6)                                                                              100 100 100 100 98  68  15  0                                      55     5(6)                                                                              100 100 100 100 100 90  27  19                                     53     5(6)                                                                              100 100 100 100 100 90  52  27                                     54     6   100 100 100 100 100 71  39  0                                      21     6   100 100 100 100 66  11  0   0                                      25     6   100 100 100 100 94  46  15  2                                      22     5   --  100 100  92 95  50  0   0                                      22     6   100 100 100  99 96  93  70  33                                     20     5(6)                                                                              100 100 100 100 99  64  25  0                                      23     5(6)                                                                              sl. 100 100 100 100 88  37  17                                                toxic                                                              24     6   100 100 100 100 100 100 64  24                                     26     6   100 100 100  95 86  51  17  6                                      27     5(6)                                                                              100 100  33  0  0   0   0   0                                      28     6   Toxic                                                                             100 100 100 94  61  0   0                                      30     5   Toxic                                                                             Toxic                                                                             Toxic                                                                             100 91  59  0   0                                      30     6   Toxic                                                                             mod.                                                                              sl. 100 100 100 99  84                                                    toxic                                                                             toxic                                                      31     5(6)                                                                              Toxic                                                                             sl. 100 100 100 96  45  8                                                     toxic                                                          17     5(6)                                                                              100 100  94  66 30  16  0   0                                      32     6   Toxic                                                                             Toxic                                                                             Toxic                                                                             100 100 100 80  40                                     33     5(6)                                                                              Toxic                                                                             Toxic                                                                             Toxic                                                                             mod.                                                                              80  48  29  12                                                            toxic                                                  34     5   Toxic                                                                             Toxic                                                                             Toxic                                                                             100 100 100 100 100                                    34     6   sl. 100 100 100 100 100 100 100                                               toxic                                                              35     5(6)                                                                              Toxic                                                                             Toxic                                                                             sl. 100 100 100 100 100                                                       toxic                                                      37     6   100 100 100 100 100 100 97  81                                     38     5(6)                                                                              Toxic                                                                             mod.                                                                              sl. sl. 100 95  40  0                                                     toxic                                                                             toxic                                                                             toxic                                                  39     6   Toxic                                                                             Toxic                                                                             mod.                                                                              mod.                                                                              100 100 100 100                                                       toxic                                                                             toxic                                                  40     6   Toxic                                                                             sl. 100 100 100 88  64  43                                                    toxic                                                          41     6    36  17  6   8  10  3   0   0                                      42     6   Toxic                                                                             Toxic                                                                             sl. 100 100 100 100 100                                                       toxic                                                      43     6   mod.                                                                              mod.                                                                              100 100 100 81  57  19                                                toxic                                                                             toxic                                                          44     6   Toxic                                                                             100 100 100 100 100 100 100                                    45     6   100 100 100 100 100 100 100 100                                    47     6   Toxic                                                                             mod.                                                                              100 100 100 100 100 100                                                   toxic                                                          49     5(6)                                                                              100 100 100 100 100 100 97  51                                     50     5(6)                                                                              Toxic                                                                             mod.                                                                              sl. 100 95  66  29  19                                                    toxic                                                                             toxic                                                      36     5(6)                                                                              Toxic                                                                             sl. 100 100 100 100 76  35                                                    toxic                                                          48     6   mod.                                                                              mod.                                                                              100 100 100 100 100 100                                               toxic                                                                             toxic                                                          51     6   100 100  93  67 18  0   0   0                                      52     5(6)                                                                              100 100  91  72 53  34  35  22                                     62     5(6)                                                                              Toxic                                                                             sl. 100 100 100 100 100 100                                                   toxic                                                          63     5(6)                                                                              100 100 100 100 100 100 100 100                                    64     5(6)                                                                              Toxic                                                                             100 100 100 100 100 100 100                                    65     5(6)                                                                              Toxic                                                                             Toxic                                                                             sl. 100 100 100 100 100                                                       toxic                                                      66     5(6)                                                                              Toxic                                                                             sl. 100 100 100 100 100 100                                                   toxic                                                          67     5(6)                                                                              mod.                                                                              sl. 100 100 100 100 100 100                                               toxic                                                                             toxic                                                          68     5(6)                                                                              Toxic                                                                             sl. 100 100 100 100 100 100                                                   toxic                                                          69     5(6)                                                                              Toxic                                                                             mod.                                                                              sl. 100 100 100 100 100                                                   toxic                                                                             toxic                                                      70     5(6)                                                                              sl. 100 100 100 100 100 100 100                                               toxic                                                              76     anti-6                                                                            Toxic                                                                             sl. 100 100 100 100 100 100                                                   toxic                                                          76     syn-6                                                                             Toxic                                                                             mod.                                                                              sl. 100 100 100 100 100                                                   toxic                                                                             toxic                                                      71     6   mod.                                                                              100 100  96 62  35  0   0                                                 toxic                                                              72     6   100 100 100 100 100 100 100 97                                     73     6   Toxic                                                                             mod.                                                                              sl. 100 88  54  2   0                                                     toxic                                                                             toxic                                                      74     6   Toxic                                                                             Toxic                                                                             Toxic                                                                             100 100 100 100 100                                    __________________________________________________________________________     *Drug concentration in micrograms per milliliter                         

Preferred sulfonylbenzimidazole compounds coming within the scope ofthis invention are those wherein R₂ is amino, R₃ is 1,3-dithiolan-2-yl,1,3-dithian-2-yl, oxadiazol-2-yl or substituted tetrazol-5-yl, C₁ -C₃alkyl, R₆ is hydrogen, phenyl or phenyl substituted by C₁ -C₄ alkyl, C₁-C₄ alkoxy, halogen (chloro, bromo, iodo), nitro or trifluoromethyl, andR₇ is hydroxy, amino, ureido or thioureido. Especially preferred are theoxime derivatives of the 5(6)-benzoyl sulfonylbenzimidazole compounds(R₆ is phenyl or substituted phenyl and R₇ is hydroxy). Illustrative ofsuch preferred compounds are the following:

1-dimethylaminosulfonyl-2-amino-5(6)-(4-chlorobenzoyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyimino-4-chlorobenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(α-methoxyiminobenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(α-thiocarbamylhydrazonobenzyl)benzimidazole,

1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-(α-methoxyimino-4-trifluoromethylbenzyl)benzimidazole,

1-dipropylaminosulfonyl-2-amino-5(6)-(3-nitrobenzoyl)benzimidazole,

1-(N-methyl-N-propylaminosulfonyl)-2-amino-5(6)-(α-hydroxyimino-3-methoxybenzyl)benzimidazole,

1-diethylaminosulfonyl-2-amino-5(6)-α-hydrazono-4-methylbenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(α-propoxyimino-4-ethoxybenzyl)benzimidazole,

1-(N-ethyl-propylaminosulfonyl)-2-amino-5(6)-(α-ethoxyimino-3-bromobenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(α-carbamylhydrazono-3-propylbenzyl)benzimidazole,

1-(N-methyl-propylaminosulfonyl)-2-amino-5(6)-(α-hydrazono-3-butoxybenzyl)benzimidazole,

1-diethylaminosulfonyl-2-amino-5(6)-(α-methoxyimino-4-nitrobenzyl)benzimidazole,

1-(N-methyl-N-propylaminosulfonyl)-2-amino-5(6)-(α-hydrazono-3-trifluoromethylbenzyl)benzimidazole,

1-dipropylaminosulfonyl-2-amino-5(6)-(α-thiocarbamylhydrazono-3-butoxybenzyl)benzimidazole,

1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-(α-hydroxyimino-3-bromobenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyimino-4-iodobenzyl)benzimidazole,

1-(N-methyl-N-propylaminosulfonyl)-2-amino-5(6)-(3-ethoxybenzoyl)benzimidazole,

1-diethylaminosulfonyl-2-amino-5(6)-(4-trifluoromethylbenzoyl)benzimidazole

1-(N-ethyl-N-propylaminosulfonyl)-2-amino-5(6)-(4-ethylbenzoyl)benzimidazole,

1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-(3-propoxybenzoyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(3,4-dichlorobenzoyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyimino-3,4-dichlorobenzyl)benzimidazole,

1-(N-methyl-N-propylaminosulfonyl)-2-amino-5(6)-(4-butylbenzoyl)benzimidazole,

1-dipropylaminosulfonyl-2-amino-5(6)-(3-butoxybenzoyl)benzimidazole,

1-(N-ethyl-N-propylaminosulfonyl)-2-amino-5(6)-(3-chloro-4-methoxybenzoyl)benzimidazole,

1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-(3-bromo-4-ethoxybenzoyl)benzimidazole,

1-diethylaminosulfonyl-2-amino-5(6)-(α-methoxyimino-3,4-dichlorobenzyl)benzimidazole,

1-(N-methyl-N-propylaminosulfonyl)-2-amino-5(6)-(α-hydroxyimino-3-bromo-4-ethoxybenzyl)benzimidazole,

1-(N-ethyl-N-propylaminosulfonyl)-2-amino-5(6)-(α-thiocarbamylhydrazono-3-methoxy-4-ethoxybenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyimino-3-chloro-4-ethoxybenzyl)benzimidazole,and

1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-(α-propoxyimino-2-iodo-4-butoxybenzyl)benzimidazole.

The sulfonylbenzimidazole compounds were tested as pure compounds and asisomer mixtures. Both isomers inhibit virus growth, the 6-isomergenerally being more active than the 5-isomer.

Compounds coming within the scope of the above formula are able tosuppress the growth of several viruses when added to a medium in whichthe virus is growing. The compounds of the invention can therefore beused in aqueous solution, preferably with a surfactant, to decontaminatesurfaces on which polio, Coxsackie, rhinovirus or other viruses arepresent, such surfaces including hospital glassware and hospital workingsurfaces and similar areas in the preparation of food.

Furthermore, the compounds can be orally administered to warm-bloodedmammals including humans in doses of 1 to 300 mg./kg. of mammalian bodyweight. The administration can be repeated periodically as needed. Inaccordance with general practice, the antiviral compound can beadministered every four to six hours.

Preferably, the compounds to be employed in accordance with the presentinvention are employed in combination with one or more adjuvants suitedto the particular route of administration. Thus, in the case of oraladministration, the compound is modified with pharmaceutical diluents orcarriers such as lactose, sucrose, starch powder, cellulose, talc,magnesium stearate, magnesium oxide, clacium sulfate, acacia powder,gelatin, sodium alginate, sodium benzoate and stearic acid. Suchcompositions can be formulated as tablets or enclosed in capsules forconvenient administration. In addition, the compounds can beadministered parenterally.

The compounds can also be mixed with a liquid and administered as nosedrops or intranasal spray.

Illustrative of the esters, hydrazides and hydroxymethyl intermediateswhich can be used to prepare the compounds of the invention are thefollowing:

ethyl 1-isopropanesulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

ethyl1-(2-acetamido-4-methylthiazol-5-yl)-sulfonyl-2propionamido-5(6)-benzimidazolecarboxylate,

ethyl1-(2-methylamino-1,3,4-thiadiazol-5-yl)-sulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

ethyl1-(N-methyl-N-propylaminosulfonyl)-2-formamido-5(6)-benzimidazolecarboxylate,

ethyl 1-piperidinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

ethyl 1-(2-furan)sulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

ethyl1-(1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

ethyl1-(N-methyl-N-ethylaminosulfonyl)-2-formamido-5(6)-benzimidazolecarboxylate,

ethyl 1-pyrrolidinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

ethyl 1-butanesulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

ethyl 1-cyclohexanesulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

ethyl 1-(2-thiophene)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

ethyl1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

ethyl1-(N-ethyl-N-propylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylate,

ethyl 1-morpholinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

ethyl 1-isobutanesulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

ethyl 1-(2-thiophene)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

ethyl1-dimethylaminosulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

1-isopropanesulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide,

1-cyclobutanesulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acidhydrazide,

1-benzenesulfonyl-2-propionamido-5(6)-benzimidazolecarboxylic acidhydrazide,

1-(2-thiazole)sulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylicacid hydrazide,

1-(N-methyl-N-propylaminosulfonyl)-2-propionamido-5(6)-benzimidazolecarboxylicacid hydrazide,

1-pyrrolidinosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide,

1-(1,3,4-thiadiazol-2-yl)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylicacid hydrazide,

1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-propionamido-5(6)-benzimidazolecarboxylicacid hydrazide,

1-diisopropylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide,

1-(3-furan)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acidhydrazide,

1-piperidinosulfonyl-2-propionamido-5(6)-benzimidazolecarboxylic acidhydrazide,

1-diethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide,

1-cyclopropanesulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acidhydrazide,

1-pentanesulfonyl-2-formamido-5(6)-benzimidazolecarboxylic acidhydrazide,

1-(3-thiophene)-sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acidhydrazide,

1-ethanesulfonyl-2-propionamido-5(6)-hydroxymethylbenzimidazole,

1-cyclopropanesulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole,

1-benzenesulfonyl-2-formamido-5(6)-hydroxymethylbenzimidazole,

1-(2-furan)sulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole,

1-(2-thiazole)sulfonyl-2-propionamido-5(6)-hydroxymethylbenzimidazole,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole,

1-(2-methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-formamido-5(6)-hydroxymethylbenzimidazole,

1-(N-methyl-N-propylaminosulfonyl)-2-acetamido-5(6)-hydroxymethylbenzimidazole,

1-dipropylaminosulfonyl-2-propionamido-5(6)-hydroxymethylbenzimidazole,

1-pyrrolidinosulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole,

1-morpholinosulfonyl-2-formamido-5(6)-hydroxymethylbenzimidazole,

1-isobutanesulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole,

1-cyclopentanesulfonyl-2-propionamido-5(6)-hydroxymethylbenzimidazole,

1-(1,3,4-thiadiazol-2-yl)sulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole,

1-(N-ethyl-N-propylaminosulfonyl)-2-formamido-5(6)-hydroxymethylbenzimidazole,

1-morpholinosulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole,

1-benzenesulfonyl-2-propionamido-5(6)-hydroxymethylbenzimidazole,

1-(4-methylthiazol-5-yl)sulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole,

1-cyclohexanesulfonyl-2-formamido-5(6)-hydroxymethylbenzimidazole,

1-diethylaminosulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole,

1-cycloheptanesulfonyl-2-propionamido-5(6)-hydroxymethylbenzimidazole,

1-diethylaminosulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole, and

1-(N-ethyl-N-isopropylaminosulfonyl)-2-formamido-5(6)-hydroxymethylbenzimidazole.

Illustrative of the 5(6)-formyl sulfonyl benzimidazole compounds andtheir derivatives provided by this invention are the following:

1-cyclohexanesulfonyl-2-formamido-5(6)-formylbenzimidazole,

1-[(2-acetamido-4-methylthiazol-2-yl)sulfonyl]-2-amino-5(6)-formylbenzimidazole,

1-diethylaminosulfonyl-2-acetamido-5(6)-formylbenzimidazole,

1-pyrrolidinosulfonyl-2-propionamido-5(6)-formylbenzimidazole,

1-cyclopentanesulfonyl-2-acetamido-5(6)-formylbenzimidazole,

1-morpholinosulfonyl-2-formamido-5(6)-formylbenzimidazole,

1-(2-thiophene)sulfonyl-2-propionamido-5(6)-formylbenzimidazole,

1-benzenesulfonyl-2-amino-5(6)-formylbenzimidazole,

1-(2-thiazole)sulfonyl-2-acetamido-5(6)-formylbenzimidazole,

1-piperidinosulfonyl-2-formamido-5(6)-formylbenzimidazole,

1-butanesulfonyl-2-amino-5(6)-formylbenzimidazole,

1-methanesulfonyl-2-acetamido-5(6)-formylbenzimidazole,

1-isopropanesulfonyl-2-propionamido-5(6)-formylbenzimidazole,

1-(2-thiophene)sulfonyl-2-amino-5(6)-formylbenzimidazole,

1-cyclopentanesulfonyl-2-acetamido-5(6)-formylbenzimidazole,

1-isopropanesulfonyl-2-amino-5(6)-formylbenzimidazole,

1-pentanesulfonyl-2-acetamido-5(6)-formylbenzimidazole,

1-ethanesulfonyl-2-formamido-5(6)-formylbenzimidazole,

1-(2-furan)sulfonyl-2-acetamido-5(6)-formylbenzimidazole,

1-benzenesulfonyl-2-propionamido-5(6)-formylbenzimidazole,

1-dipropylaminosulfonyl-2-acetamido-5(6)-formylbenzimidazole,

1-pyrrolidinosulfonyl-2-amino-5(6)-(hydrazonomethyl)benzimidazole,

1-piperidinosulfonyl-2-acetamido-5(6)-(1,3-dithiolan-2-yl)benzimidazole,

1-morpholinosulfonyl-2-formamido-5(6)-(1,3-dithian-2-yl)benzimidazole,

1-dimethylaminosulfonyl-2-propionamido-5(6)-(isopropoxyiminomethyl)benzimidazole,

1-cyclopropanesulfonyl-2-formamido-5(6)-(thiocarbamylhydrazonomethyl)benzimidazole,

1-(2-thiazole)sulfonyl-2-acetamido-5(6)-(1,3-dithiolan-2-yl)benzimidazole,

1-isopropanesulfonyl-2-amino-5(6)-(1,3-dithian-2-yl)benzimidazole,

1-dimethylaminosulfonyl-2-propionamido-5(6)-(methoxyiminomethyl)benzimidazole,

1-benzenesulfonyl-2-formamido-5(6)-(hydroxyiminomethyl)benzimidazole,

1-isopropanesulfonyl-2-amino-5(6)-(hydroxyiminomethyl)benzimidazole,

1-isopropanesulfonyl-2-acetamido-5(6)-(hydrazonomethyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(hydrazonomethyl)benzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5(6)-(carbamylhydrazonomethyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(thiocarbamylhydrazonomethyl)benzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5(6)-hydroxyiminomethyl)benzimidazole,

1-diethylaminosulfonyl-2-amino-5(6)-(methoxyiminomethyl)benzimidazole,

1-dipropylamino-2-acetamido-5(6)-(ethoxyiminomethyl)benzimidazole,

1-diisopropylaminosulfonyl-2-propionamido-5(6)-(propoxyiminomethyl)benzimidazole,

1-cyclobutanesulfonyl-2-amino-5(6)-(isopropoxyiminomethyl)benzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5(6)-(butoxyiminomethyl)benzimidazole,

1-piperidinosulfonyl-2-formamido-5(6)-(isobutoxyiminomethyl)benzimidazole,

1-(2-thiophene)sulfonyl-2-acetamido-5(6)-(sec-butoxyiminomethyl)benzimidazole,

1-(2-acetamido-4-methylthiazol-2-yl)sulfonyl-2-amino-5(6)-(tert-butoxyiminomethyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(1,3-dithiolan-2-yl)benzimidazole,

1-dimethylamino-2-acetamido-5(6)-(1,3-dithian-2-yl)benzimidazole,

1-isopropanesulfonyl-2-acetamido-5(6)-(1,3-dithiolan-2-yl)benzimidazole,and

1-cyclohexanesulfonyl-2-formamido-5(6)-(1,3-dithian-2-yl)benzimidazole.

Illustrative of the 5(6)-keto sulfonylbenzimidazole compounds and theirderivatives provided by this invention are the following:

1-isopropanesulfonyl-2-amino-5(6)-acetylbenzimidazole,

1-cyclopentanesulfonyl-2-acetamido-5(6)-propionylbenzimidazole,

1-cyclopropanesulfonyl-2-formamido-5(6)-isopropionylbenzimidazole,

1-dimethylaminosulfonyl-2-acetamido 5(6)-butyrylbenzimidazole,

1-piperidinosulfonyl-2-propionamido-5(6)-isobutyrylbenzimidazole,

1-diethylaminosulfonyl-2-amino-5(6)-pentanoylbenzimidazole,

1-dipropylaminosulfonyl-2-formamido-5(6)-hexanoylbenzimidazole,

1-pentanesulfonyl-2-amino-5(6)-heptanoylbenzimidazole,

1-(2-thiophene)sulfonyl-2-acetamido-5(6)-octanoylbenzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-cyclopropylcarbonylbenzimidazole,

1-piperidinosulfonyl-2-propionamido-5(6)-isopentanoylbenzimidazole,

1-diethylaminosulfonyl-2-amino-5(6)-cyclopropylcarbonylbenzimidazole,

1-(2-thiophene)sulfonyl-2-acetamido-5(6)-cyclobutylcarbonylbenzimidazole,

1(2-thiazole)sulfonyl-2-formamido-5(6)-cyclopentylcarbonylbenzimidazole,

1-(2-acetamido-4-methylthiazol-2-yl)sulfonyl-2-propionamido-5(6)-cyclohexylcarbonylbenzimidazole,

1-(5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl-2-formamido-5(6)-cycloheptylcarbonylbenzimidazole,

1-(3-furan)sulfonyl-2-amino-5(6)-(1-hydrazonoethyl)benzimidazole,

1-cyclohexanesulfonyl-2-acetamido-5(6)-(1-hydroxyiminopropyl)benzimidazole,

1-isopropanesulfonyl-2-propionamido-5(6)-(1-methoxyiminoisopropyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(1-ethoxyiminobutyl)benzimidazole,

1-piperidinosulfonyl-2-propionamido-5(6)-(1-propoxyiminosibutyl)benzimidazole,

1-(5-methylamino-1,3,4-thiadiazol-2-yl)sulfonyl-2-amino-5(6)-(1-isopropoxyiminopentyl)benzimidazole,

1-benzenesulfonyl-2-acetamido-5(6)-(1-butoxyiminohexyl)benzimidazole,

1-cyclopropanesulfonyl-2-formamido-5(6)-(1-carbamylhydrazonoheptyl)benzimidazole,

1-(3-thiophene)sulfonyl-2-acetamido-5(6)-(1-thiocarbamylhydrazonoethyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydrazonocyclopentylmethyl)benzimidazole,

1-cyclobutanesulfonyl-2-acetamido-5(6)-(α-hydroxyiminocyclobutylmethyl)benzimidazole,

1-(2-furan)sulfonyl-2-formamido-5(6)-(α-methoxyiminocyclopentylmethyl)benzimidazole,

1-diethylaminosulfonyl-2-propionamido-5(6)-(α-ethoxyiminocyclohexylmethyl)benzimidazole,

1-morpholinosulfonyl-2-amino-5(6)-(α-propoxyiminocyclopentylmethyl)benzimidazole,

1-(2-thiazole)sulfonyl-2-acetamido-5(6)-(1-isopropoxyiminoisobutyl)benzimidazole,

1-(5-methylamino-1,3,4-thiadiazol-2-yl)sulfonyl-2-formamido-5(6)-(1-butoxyiminoisopropyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-[ζ-(thiocarbamylhydrazono)cyclopentylmethyl]benzimidazole,

1-diisopropylaminosulfonyl-2-acetamido-5(6)-[α-(carbamylhydrazono)cyclobutylmethyl]benzimidazole,

1-pyrrolidinosulfonyl-2-propionamido-5(6)-(1-hydroxyiminoisoamyl)benzimidazole,

1-butanesulfonyl-2-formamido-5(6)-(1-hydrazonooctyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(1-hydrazonopropyl)benzimidazole,

1-(2-acetamido-4-methylthiazol-2-yl)sulfonyl-2-amino-5(6)-[(α-methoxyimino)cyclopropylmethyl]benzimidazole,

1-cycloheptanesulfonyl-2-formamido-5(6)-(1-carbamylhydrazonoethyl)benzimidazole,

1-(2-thiophene)sulfonyl-2-propionamido-5(6)-(1-thiocarbamylhydrazonoethyl)benzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5(6)-[(α-butoxyimino)cycloheptylethyl]benzimidazole,

1-pyrrolidinosulfonyl-2-amino-5(6)-(1-hydroxyiminopropyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-[(α-ethoxyimino)cyclohexylmethyl]benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-cyclopropylacetylbenzimidazole,

1-isopropanesulfonyl-2-acetamido-5(6)-cyclobutylacetylbenzimidazole,

1-methanesulfonyl-2-formamido-5(6)-cyclopentylacetylbenzimidazole,

1-(2-thiophene)sulfonyl-2-methyl-5(6)-cyclohexylacetylbenzimidazole,

1-piperidinosulfonyl-2-amino-5(6)-cycloheptylacetylbenzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-[(1-hydrazono-2-cyclopropyl)ethyl]benzimidazole,

1-isopropanesulfonyl-2-propionamido-5(6)-[(1-hydroxyimino-2-cyclobutyl)ethyl]benzimidazole,

1-benzenesulfonyl-2-amino-5(6)-[(1-methoxyimino-2-cyclopentyl)ethyl]benzimidazole,

1-[(2-furan)sulfonyl]-2-amino-5(6)-[(1ethoxyimino-2-cyclohexyl)ethyl]benzimidazole,

1-piperidinosulfonyl-2-formamido-5(6)-[(1-propoxyimino-2-cycloheptyl)ethyl]benzimidazole,

1-[(5-methyl-1,3,4-thiadiazol-5-yl)sulfonyl]-2-amino-5(6)-[(1-isopropoxy-2-cyclopropyl)ethyl]benzimidazole,

1-pyrrolidinosulfonyl-2-propionamido-5(6)-[(1-butoxyimino-2-cyclobutyl)ethyl]benzimidazole

1-dimethylaminosulfonyl-2-amino-5(6)-[(1-carbamylhydrazono-2-cyclopropyl)ethyl]benzimidazole,

1-morpholinosulfonyl-2-amino-5(6)-[(1-thiocarbamylhydrazono-2-cyclopentyl)ethyl]benzimidazole,

1-dimethylaminosulfonyl-2-propionamido-5(6)-(2-cyclopropylpropionyl)benzimidazole,

1-isopropanesulfonyl-2-amino-5(6)-(2-cyclobutylpropionyl)benzimidazole,

1-benzenesulfonyl-2-acetamido-5(6)-(2-cyclopentylpropionyl)benzimidazole,

1(3-furan)sulfonyl-2-amino-5(6)-(2-cyclohexylpropionyl)benzimidazole,

1-(5-methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-(2-cycloheptylpropionyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-[(1-hydrazono-2-cyclopropyl)propyl]benzimidazole,

1-isopropanesulfonyl-2-acetamido-5(6)-[(1-hydroxyimino-2-cyclobutyl)propyl]benzimidazole,

1-(2-acetamido-4-methylthiazol-2-yl)sulfonyl-2-formamido-5(6)-[(1-methoxyimino-2-cyclopentyl)propyl]benzimidazole,

1-piperidinosulfonyl-2-amino-5(6)-[(1-ethoxyimino-2-cyclohexyl)propyl]benzimidazole,

1-benzenesulfonyl-2-propionamido-5(6)-[(1-propoxyimino-2-cycloheptyl)propyl]benzimidazole,

1-butanesulfonyl-2-amino-5(6)-[(1-butoxyimino-2-cyclopropyl)propyl]benzimidazole,

1-[(2-thiazole)sulfonyl]-2-acetamido-5(6)-[(1-carbamylhydrazono-2-cyclopropyl)propyl]benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-[(1-thiocarbamylhydrazono-2-cyclopentyl)propyl]benzimidazole,

1-pyrrolidinosulfonyl-2-propionamido-5(6)-[1-carbamylhydrazono-2-cyclohexyl)propyl]benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(n-pentanoyloxyiminobenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(pivaloyloxyiminobenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(3-methoxycarbonylpropionyloxyiminobenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-[2-(p-nitrobenzyloxycarbonyl)ethylcarbonyloxyiminobenzyl]benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(benzyloxycarbonylaminomethylcarbonyloxyiminobenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-(phthalimidomethylcarbonyloxyiminobenzyl)benzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-[2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxyiminobenzyl]benzimidazole,

1-isopropylsulfonyl-2-amino-6-[α-(3-pentylidene)benzyl]benzimidazole,

1-isopropylsulfonyl-2-amino-6-(α-isopropylidenebenzyl)benzimidazole,

1-isopropylsulfonyl-2-amino-6-(α-isopropyl-α-hydroxybenzyl)benzimidazole,and

1-dimethylaminosulfonyl-2-amino-6-[α-(3-pentylidene)benzyl]benzimidazole.

Illustrative of the 5(6)-heterocyclic sulfonylbenzimidazole compoundsprovided by this invention are the following:

1-isopropanesulfonyl-2-amino-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazole,

1-cyclopentanesulfonyl-2-formamido-5(6)-(2-methyl-1,3,4-oxadiazol-5-yl)benzimidazole,

1-benzenesulfonyl-2-acetamido-5(6)-(2-ethyl-1,3,4-oxadiazol-5-yl)benzimidazole,

1-(2-furan)sulfonyl-2-propionamido-5(6)-(2-propyl-1,3,4-oxadiazol-5-yl)benzimidazole,

1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-(2-butyl-1,3,4-oxadiazol-5-)benzimidazole,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-formamido-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazole,

1-diethylaminosulfonyl-2-acetamido-5(6)-(2-methyl-1,3,4-oxadiazol-5-yl)benzimidazole,

1-(N-methyl-N-isopropylaminosulfonyl)-2-propionamido-5(6)-(2-propyl-1,3,4-oxadiazol-5-yl)benzimidazole,

1-piperidinosulfonyl-2-amino-5(6)-(2-butyl-1,3,4-oxadiazol-5-yl)benzimidazole,

1-butanesulfonyl-2-formamido-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazole,

1-cyclopropanesulfonyl-2-acetamido-5(6)-(2-methyl-1,3,4-oxadiazol-5-yl)benzimidazole,

1-ethanesulfonyl-2-amino-5(6)-(tetrazol-5-yl)benzimidazole,

1-cyclobutanesulfonyl-2-formamido-5(6)-[1(2)-methyltetrazol-5-yl]benzimidazole,

1-benzenesulfonyl-2-acetamido-5(6)-[(1(2)-propyltetrazol-5-yl]benzimidazole

1-(2-thiophene)sulfonyl-2-propionamido-5(6)-[1(2)-butyltetrazol-5-yl]benzimidazole,

1-(2-acetamido-4-methyltetrazol-5-yl)sulfonyl-2-amino-5(6)-(tetrazol-5-yl)benzimidazole,

1-(2-acetamido-4-methyltetrazol-5-yl)sulfonyl-2-amino-5(6)-(tetrazol-5-yl)benzimidazole,

1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-formamido-5(6)-[1(2)-methyltetrazol-5-yl]benzimidazole,

1-diisopropylaminosulfonyl-2-acetamido-5(6)-[1(2)-ethyltetrazol-5-yl]benzimidazole,

1-(N-ethyl-N-propylaminosulfonyl)-2-propionamido-5(6)-[1(2)-propyltetrazol-5-yl]benzimidazole,

1-pyrrolidinosulfonyl-2-amino-5(6)-[1(2)-butyltetrazol-5-yl]benzimidazole,

1-morpholinosulfonyl-2-formamido-5(6)-(tetrazol-5-yl)benzimidazole,

1-isopropanesulfonyl-2-acetamido-5(6)-[1(2)-methyltetrazol-5-yl]benzimidazole,

1-cyclopropanesulfonyl-2-propionamido-5(6)-[1(2)-ethyltetrazol-5-yl]benzimidazole,

1-cycloheptanesulfonyl-2-amino-5(6)-[1(2)-propyltetrazol-5-yl]benzimidazole, and

1-(2-thiazole)sulfonyl-2-formamido-5(6)-[1(2)-butyltetrazol-5-yl]benzimidazole.

Illustrative of the 5(6)-hydroxy sulfonylbenzimidazole compounds and theesters derived therefrom provided by this invention are the following:

1-ethanesulfonyl-2-amino-5(6)-hydroxybenzimidazole,

1-isopropanesulfonyl-2-formamido-5(6)-hydroxybenzimidazole,

1-pentanesulfonyl-2-acetamido-5(6)-hydroxybenzimidazole,

1-cyclobutanesulfonyl-2-propionamido-5(6)-hydroxybenzimidazole,

1-cyclohexanesulfonyl-2-amino-5(6)-hydroxybenzimidazole,

1-benzenesulfonyl-2-formamido-5(6)-hydroxybenzimidazole,

1-(3-furan)sulfonyl-2-acetamido-5(6)-hydroxybenzimidazole,

1-(2-thiophene)sulfonyl-2-propionamido-5(6)-hydroxybenzimidazole,

1(2-acetamido-4-methylthiazol-5-yl)-2-amino-5(6)-hydroxybenzimidazole,

1-(2-methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-formamido-5(6)-hydroxybenzimidazole,

1-diisopropylaminosulfonyl-2-acetamido-5(6)-hydroxybenzimidazole,

1-(N-methyl-N-isopropylaminosulfonyl)-2-propionamido-5(6)-hydroxybenzimidazole,

1-piperidinosulfonyl-2-amino-5(6)-hydroxybenzimidazole,

1-morpholinosulfonyl-2-formamido-5(6)-hydroxybenzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-propionyloxybenzimidazole,

1-isopropanesulfonyl-2-acetamido-5(6)-phenylacetoxybenzimidazole,

1-cyclopropanesulfonyl-2-formamido-5(6)-benzoyloxybenzimidazole,

1-benzenesulfonyl-2-propionamido-5(6)-pentanoyloxybenzimidazole,

1-(3-furan)sulfonyl-2-amino-5(6)-phenylacetoxybenzimidazole,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-amino-5(6)-benzoyloxybenzimidazole,

1-piperidinosulfonyl-2-formamido-5(6)-heptanoyloxybenzimidazole,

1-cyclopentanesulfonyl-2-propionamido-5(6)-acetoxybenzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-phenylacetoxybenzimidazole,

1-dimethylamino-2-amino-5(6)-benzoyloxybenzimidazole,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-acetamido-5(6)-octanoyloxybenzimidazole,

1-pyrrolidinosulfonyl-2-formamido-5(6)-phenylacetoxybenzimidazole,

1-cyclobutanesulfonyl-2-amino-5(6)-benzoyloxybenzimidazole,

1-(2-thiophene)sulfonyl-2-acetamido-5(6)-propionyloxybenzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-octanoyloxybenzimidazole,

The following examples further illustrate the preparation of thestarting materials, intermediates, and compounds of the invention. Theterm "m/e" used in characterizing the products refers to themass-to-charge ratio of ions which appear in the mass spectra of theproducts. In general, the values correspond to molecular weights of themajor peaks.

EXAMPLE 1 Ethyl1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate.

One hundred and forty grams (0.68 mole) of ethyl2-amino-5(6)-benzimidazolecarboxylate was stirred in 500 ml. of acetoneand 77 ml. of triethylamine. One hundred grams of dimethylsulfamoylchloride dissolved in 100 ml. of acetone was added through a droppingfunnel to the stirred reaction mixture. The reaction mixture wasrefluxed for about 100 hours. The hot mixture was filtered to yieldsolid A. The filtrate was allowed to cool and solid B crystallized outovernight. Solids A and B were combined and washed with water to removetriethylamine hydrochloride. The product was dissolved in about 1.5 l ofhot 2B ethanol. The hot ethanol solution was filtered to separateinsoluble material. The ethanol filtrate was allowed to cool whereuponproduct crystallized. The product was collected to give 23 g. of ethyl1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate, mp.215°-217° C.

Analysis: C₁₂ H₁₆ N₄ O₄ S MW 312. Calcd: C, 46.14; H, 5.16; N, 17.94.Found: C, 45.87, H, 5.05, N, 18.21.

The ethanol filtrate was evaporated in vacuo to a small volume to yield15 g. of the 5-isomer, ethyl1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxylate, mp.167°-168° C. The 5-isomer was characterized by nmr and elementalanalysis. The total yield of product was 38 g. (18 percent).

                                      EXAMPLES 2-10                               __________________________________________________________________________    The following Ethyl 1-(Substituted-Sulfonyl)-2-Amino-                         5(6)-Benzimidazolecarboxylates were prepared by the method of Example 1.                            Analysis (Percent)                                                      MP   Theory   Found                                           No.                                                                              Sulfonyl Substituent                                                                       °C.                                                                         C  H  N  C  H  N                                         __________________________________________________________________________    2  isopropyl*   166-168                                                                            50.15                                                                            5.50                                                                             13.50                                                                            49.86                                                                            5.48                                                                             13.24                                     3  isopropyl**  165-167                                                                            50.15                                                                            5.50                                                                             13.50                                                                            49.92                                                                            5.26                                                                             13.44                                     4  benzene           55.64                                                                            4.38                                                                             12.17                                                                            55.86                                                                            4.48                                                                             12.22                                     5  (N-methyl-N-ethylamino)                                                                         47.84                                                                            5.56                                                                             17.17                                                                            48.09                                                                            5.49                                                                             16.97                                     6  diethylamino 142-143                                                                            49.40                                                                            5.92                                                                             16.46                                                                            49.73                                                                            5.90                                                                             16.18                                     7  (N-methyl-N-propyl-                                                           amino)       140-148                                                                            49.40                                                                            5.92                                                                             16.46                                                                            49.30                                                                            6.13                                                                             16.37                                     8  2-thiophene       47.85                                                                            3.73                                                                             11.96                                                                            47.67                                                                            3.84                                                                             11.76                                     9  (2-acetamido-4-methyl-                                                        thiazol-5-yl)     45.39                                                                            4.02                                                                             16.54                                                                            45.52                                                                            4.43                                                                             15.94                                     10 (2-methylamino-1,3,4-                                                         thiadiazol-5-yl)  40.83                                                                            3.69                                                                             21.98                                                                            40.59                                                                            3.94                                                                             21.78                                     __________________________________________________________________________     *5-isomer, **6isomer, other esters are 5(6)isomeric mixtures.                 The esters of Example 1-10 can be chemically reduced by the method of         Example 11 to provide the corresponding 5(6)hydroxymethyl                     sulfonylbenzimidazole compounds.                                         

EXAMPLE 111-Dimethylaminosulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole (A)2-Amino-5(6)-hydroxymethylbenzimidazole

Twenty-four and six-tenths grams of ethyl2-amino-5(6)-benzimidazolecarboxylate was suspended in 600 ml. oftetrahydrofuran (THF) under nitrogen. Ninety-six ml. (0.36 mole) ofsodium bis(2-methoxyethoxy)-aluminum hydride (RED-AL) in 400 ml. of THFwas added dropwise to the stirred reaction mixture at a rate such thatthe temperature did not exceed 35° C. The mixture was heated at refluxfor about 20 hours. The excess RED-AL was decomposed by the addition of30 ml. of water. The mixture was filtered and the filtrate wasevaporated to dryness in vacuo. The foamy residue was treated with 150ml. of ethyl acetate and 200 ml. of water. The aqueous emulsified phasewas separated. The aqueous phase was filtered to yield a yellow solid.The aqueous filtrate was evaporated in vacuo to yield a second crop. Thecombined yield was 12.3 g. (65 percent) of crude2-amino-5(6)-hydroxymethylbenzimidazole. An analytical sample of theisomeric mixture was prepared.

Analysis: C₈ H₉ N₃ O MW 163. Calcd.: C, 58.88; H, 5.56; N, 25.75. Found:C, 58.65; H, 5.48; N, 25.54.

(B) 1-Dimethylaminosulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole

Thirty millimoles, 4.9 g., of 2-amino-5(6)-hydroxymethylbenzimidazolewere dissolved in 40 ml. of acetone and thirty millimoles, 3.03 g.,triethylamine. To the acetone solution were added 4.32 g. (30 mmoles) ofdimethylsulfamoyl chloride. The mixture was heated at reflux for about17 hours. The mixture was poured in 25 ml. of water. The aqueous mixturewas extracted with chloroform. The chloroform extract was washedsuccessively with water and saturated sodium chloride solution. Thechloroform solution was filtered and dried. The chloroform wasevaporated to dryness in vacuo, to yield 5.5 g. (66 percent) of crudeproduct as an isomeric mixture.

Seven grams of crude isomeric mixture were chromatographed over Woelmsilica gel using ethyl acetate as the eluant. The 6-isomer was collectedafter 6 l. of eluant had passed over the column. The yield was 1.02 g.of 1-dimethylaminosulfonyl-2-amino-6-hydroxymethylbenzimidazole, mp.182-183° C. (ethyl acetate-methanol)

Analysis: C₁₀ H₁₄ N₄ O₃ S MW 270. Calcd.: C, 44.43; H, 5.22; N, 20.73.Found: C, 44.37; H, 5.18; N, 20.44.

EXAMPLE 12 2-Amino-5(6)-hydroxymethylbenzimidazole (A)4-Amino-3-nitrobenzyl alcohol

Fifty grams (0.27 mole) of 4-chloro-3-nitrobenzyl alcohol, 250 ml. ofmethanol and 200 ml. of liquid ammonia were loaded into a coldautoclave. The autoclave was sealed and heated to a temperature of 150°C. The reaction was continued for 6 hours. After cooling the autoclavewas vented and the reaction mixture was evaporated in vacuo. The residuewas taken up in ether and the ether solution was filtered to separatethe ammonium chloride. The ether filtrate was evaporated in vacuo toyield a solid product. The product was recrystallized from 2-Bethanol/ethyl acetate to give 23.6 g. (52 percent yield) of4-amino-3-nitrobenzyl alcohol, mp. 100°-101° C.

Analysis: C₇ H₈ N₂ O₃ MW 168. Calcd: C, 50.00; H, 4.80; N, 16.66. Found:C, 49.72; H, 4.56; N, 16.44.

(B) 3,4-Diaminobenzyl alcohol

Six grams (0.035 mole) of 4-amino-3-nitrobenzyl alcohol, 95 ml. oftetrahydrofuran and 0.5 g. of Raney Nickel were hydrogenated at 40 psiat room temperature until 3 moles of hydrogen were absorbed. Thecatalyst was filtered and the filtrate was evaporated in vacuo to yield4.83 g. (82 percent yield) of 3,4-diaminobenzyl alcohol, mp. 74°-75° C.

Analysis: C₇ H₁₀ N₂ O MW 138. Calcd: C, 60.85; H, 7.30; N, 20.28. Found:C, 60.90; H, 7.15; N, 19.99.

(C) 2-Amino-5(6)-hydroxymethylbenzimidazole.

Two grams (0.014 mole) of 3,4-diaminobenzyl alcohol were dissolved in 40ml. of methanol. To this solution was added a solution of 1.6 g. (0.014mole) of cyanogen bromide in 10 ml. of methanol. After standingovernight at room temperature, the reaction mixture was evaporated todryness in vacuo to give 3.4 g. (97 percent yield) of the hydrobromidesalt of 2-amino-5(6)-hydroxymethylbenzimidazole.

Alternatively, this product may also be obtained from4-amino-3-nitrobenzyl alcohol without isolation of the intermediatediamine after hydrogenation. The filtrate obtained after removal of thehydrogenation catalyst was treated with a solution of cyanogen bromidein methanol. The product was isolated as described above.

EXAMPLE 13 1-Dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole

Two hundred and fifty milligrams of1-dimethylaminosulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole weresuspended in 7 ml. of acetone and the mixture was cooled in an ice bath.Jones reagent (0.3 ml.) was added to the cold reaction mixture and thereaction was continued at 0° C. for about 5 minutes. The mixture waspoured into 40 ml. of water. The aqueous mixture was extracted withchloroform (40 ml. portions). The chloroform extract was washed withwater and saturated sodium chloride solution and dried. The chloroformwas evaporated in vacuo to leave a solid residue. The residue wasrecrystallized from ethyl acetate to yield 57 mg. (1st crop) of1-dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole.

Analysis C₁₀ H₁₂ N₄ O₃ S MW 268. Calcd: C, 44.71; H, 4.51; N, 20.88Found: C, 44.75; H, 4.52; N, 20.63

EXAMPLE 141-Dimethylaminosulfonyl-2-amino-5(6)-(hydroxyiminomethyl)benzimidazole

One millimole, 268 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole, 101 mg. (1mmole) of triethylamine, 69 mg. (1 mmole) of hydroxylamine hydrochlorideand 5 drops of water were heated under reflux for about 20 hours. Thecooled reaction mixture was filtered to give 140 mg. of the oximeproduct. The filtrate was poured in 30 ml. of water. The aqueous mixturewas extracted with ethyl acetate. The organic phase was washed withwater and dried (MgSO₄). The ethyl acetate was evaporated in vacuo togive an additional 87 mg. of the oxime product.

Analysis: C₁₀ H₁₃ N₅ O₃ S MW 263. Calcd: C, 42.55; H, 4.28; N, 24.81.Found: C, 42.03; H, 4.31; N, 23.91.

EXAMPLE 151-Dimethylaminosulfonyl-2-amino-5(6)-(hydrazonomethyl)benzimidazole

One millimole, 268 mg., of1-dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole, 20 ml. ofmethanol, and 32 mg. of hydrazine were heated at reflux for about 16hours. The reaction mixture was evaporated in vacuo to about one-fourththe original volume. The mixture was poured into 30 ml. of water. Theprecipitated product was collected to give 80 mg. of the hydrazoneproduct. The aqueous filtrate was evaporated to dryness in vacuo to givean additional 75 mg. of the hydrazone derivative. m/e 282.

EXAMPLE 161-Dimethylaminosulfonyl-2-amino-5(6)-thiocarbamylhydrazonomethylbenzimidazole

Two hundred and fifty milligrams of1-dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole, 15 ml. ofmethanol, and 70 mg. of thiosemicarbazide was heated at reflux for about3 hours. The thiosemicarbazone product precipitated upon cooling and wascollected to give 170 mg. of solid. The thiosemicarbazone wasrecrystallized from a mixture of methanol (6 ml.) and chloroform (2 ml.)to yield 100 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-thiocarbamylhydrazonomethylbenzimidazole.

Analysis C₁₁ H₁₅ N₇ O₂ S₂ MW 341. Calcd: C, 38.70; H, 4.43; N, 28.72Found: C, 38.87; H, 4.64; N, 28.57

EXAMPLE 171-Dimethylaminosulfonyl-2-amino-5(6)-carbamylhydrazonomethylbenzimidazole

Two millimoles, 536 mg., of1-dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole, 4 ml. ofmethanol, 222 mg. of semicarbazide, and 0.5 ml. of water were heatedunder reflux for about 2 hours. Two milliliters of methanol were addedto the cooled reaction mixture and the precipitated product wascollected. The product was washed with cold methanol to yield 226 mg. ofthe semicarbazone product. The combined filtrates were evaporated invacuo to a small volume. The residue was treated with 50 ml. ofsaturated sodium chloride solution. The aqueous solution was extractedwith methylene chloride. The extract was washed with water and saturatedsodium chloride solution and dried. The methylene chloride wasevaporated to dryness in vacuo to give a second crop, 160 mg., of1-dimethylaminosulfonyl-2-amino-5(6)-carbamylhydrazonomethylbenzimidazole.m/e 325.

EXAMPLE 181-Dimethylaminosulfonyl-2-amino-5(6)-(1,3-dithiolan-2-yl)benzimidazole

One millimole, 268 mg., of1-dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole, 5 ml. ofmethanol, 0.2 ml. of ethanedithiol and 0.2 ml. of boron trifluorideetherate were reacted at room temperature for about 2 hours. The productprecipitated out of solution and was filtered. The solid product waswashed with cold methanol to give 65 mg. of the cyclic thioacetal,1-dimethylaminosulfonyl-2-amino-5(6)-(dithiolan-2-yl)benzimidazole. Thewashings and filtrates were combined and mixed with 20 ml. of saturatedsodium carbonate solution. The aqueous solution was extracted with ethylacetate. The extract was washed with saturated sodium chloride solutionand dried (MgSO₄). The ethyl acetate was evaporated to dryness in vacuo.The solid residue was reated with methanol and the methanol insolublematerial was collected, yield 155 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(1,3-dithiolan-2-yl)benzimidazole.The methanol filtrate was evaporated to dryness in vacuo to give 95 mg.of additional product. m/e 344.

EXAMPLE 191-Dimethylaminosulfonyl-2-amino-5(6)-(1,3-dithian-2-yl)benzimidazole

Two hundred and twenty milligrams (0.8 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole, 2 ml. ofmethanol, 0.15 ml. (1.6 mmole) of 1,3-propanedithiol, and 0.75 ml. ofboron trifluoride etherate were reacted at room temperature. About 6 ml.of ether was added to the mixture which was allowed to react for about 2hours. The reaction mixture was diluted to a volume of 12 ml. with etherand product precipitated out of solution. The mixture was centrifugedand the supernatant liquid was decanted. The precipitate was suspendedin ether and the mixture was again centrifuged. The supernatant liquidwas decanted and the solid product was dried under vacuum to yield 224mg. (75 percent) of the cyclic thioacetal product,1-dimethylaminosulfonyl-2-amino-5(6)-(1,3-dithian-2-yl)benzimidazole.m/e 358.

EXAMPLE 201-Dimethylaminosulfonyl-2-amino-5(6)-methoxyiminomethylbenzimidazole

A solution of 135 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-formylbenzimidazole andmethoxyamine hydrochloride in 20 ml. of methanol was refluxed for 17hours. The color of the solution changed from red to yellow. Thereaction mixture was concentrated to one-half its volume and then 9 ml.of a buffer solution (pH=7.00) was added. The mixture was concentratedby evaporation, filtered, washed with water and dried to yield 42 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-methoxyiminomethylbenzimidazole.m/e 297.

EXAMPLE 21 1-Dimethylaminosulfonyl-2-amino-5(6)-acetylbenzimidazole (A)4-Acetamidoacetophenone

One hundred grams of p-aminoacetophenone was added portionwise to 400ml. of acetic anhydride. Pyridine was added to maintain a homogeneoussolution. The reaction mixture was stirred for 2 hours to roomtemperature. The mixture was poured into 3.5 l. of cold water. Theprecipitated product was collected to yield 108.5 g. (93 percent) of4-acetamidoacetophenone.

Analysis C₁₀ H₁₁ NO₂ MW 177. Calcd: C, 67.78; H, 6.26; N, 7.90. Found:C, 68.03; H, 6.47; N, 8.02.

(B) 3-Nitro-4-acetamidoacetophenone

Five grams of 4-acetamidoacetophenone were added portionwise to 25 ml.of red fuming nitric acid at 0°-5° C. After the addition was completedthe mixture was stirred for about 15 minutes. The reaction mixture wascarefully poured over ice. The precipitated product was collected toyield 4.7 g. (75 percent) of 3-nitro-4-acetamidoacetophenone.

(C) 3-Nitro-4aminoacetophenone

Sixteen grams of 3-nitro-4-acetamidoacetophenone in 160 ml. ofconcentrated sulfuric acid were stirred at room temperature for aboutone hour. The mixture was carefully poured into cold water and theprecipitated product was filtered to yield 9.5 g. (73 percent) of3-nitro-4-aminoacetophenone.

Analysis C₈ H₈ N₂ O₃ MW 180. Calcd: C, 53.33; H, 4.48; N, 15.55. Found:C, 53.18; H, 4.33; N, 15.87.

(D) 2-Amino-5(6)-acetylbenzimidazole

Four and one-half grams of 3-nitro-4aminoacetophenone were hydrogenatedat 60 psi in 145 ml. of ethyl acetate with 1 g. of platinum oxide and 3g. of Raney nickel at room temperature. Three equivalents of hydrogenwere absorbed in 5 hours. The catalyst was filtered. Three grams ofcyanogen bromide was added to the filtrate and the mixture was stirredfor about 24 hours. The hydrobromide salt of the product precipitatedand was collected to yield 2 g. of 2-amino-5(6)-acetylbenzimidazolehydrobromide.

Analysis C₉ H₉ N₃ O.HBr MW 256. Calcd: C, 42.21; H, 3.94; N, 16.41.Found: C, 42.43; H, 4.09; N, 16.35.

(E) 1-Dimethylaminosulfonyl-2-amino-5(6)-acetylbenzimidazole

Four grams (15.6 mmole) of 2-amino-5(6)-acetylbenzimidazolehydrobromide, 50 ml. of acetone, 5 ml. (35.6 mmole) of triethylamine and2.3 g. (16.0 mmole) of dimethylsulfamoyl chloride were refluxed forabout 12 hours. The mixture was filtered and the filtrate was evaporatedin vacuo to a solid residue. The residue was taken up in 80 ml. ofmethanol. The methanol solution was concentrated to about 60 ml. andcooled. The product crystallized to yield 800 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-acetylbenzimidazole, yellowcrystals, mp. 206°-210° C. (dec).

Analysis C₁₁ H₁₄ N₄ O₃ S MW 282. Calcd: C, 46.80; H, 5.00; N, 19.85.Found: C, 47.07; H, 4.99; N, 19.65.

EXAMPLE 22 1-Dimethylaminosulfonyl-2-amino-5(6)-propionylbenzimidazole

(A) Beginning with p-aminopropiophenone according to Example 20, tengrams (0.053 mole) of 2-amino-5(6)-propionylbenzimidazole, 100 ml. ofacetone, 10 ml. of triethylamine and 8.6 g. of dimethylsulfamoylchloride were reacted to yield the crude product. Recrystallization from600 ml. of methanol gave about 6.0 g. of the 5-isomer,1-dimethylaminosulfonyl-2-amino-5-propionylbenzimidazole, mp. 206°-208°C.

Analysis C₁₂ H₁₈ N₄ O₃ S MW 296. Calcd: C, 48.64; H, 5.44; N, 18.91.Found: C, 48.41; H, 5.49; N, 18.73.

(B) There was obtained 2.8 g of methanol insoluble material from thecrystallization above which proved to be the 6-isomer,1-dimethylaminosulfonyl-2-amino-6-propionylbenzimidazole, confirmed byNMR.

Analysis C₁₂ H₁₈ N₄ O₃ S MW 296. Calcd: C, 48.64; H, 5.44; N, 18.91.Found: C, 48.58; H, 5.63; N, 18.71.

EXAMPLE 23 1-Dimethylaminosulfonyl-2-amino-5(6)-butyrylbenzimidazole

When 5.7 g. of 2-amino-5(6)-butyrylbenzimidazole, 30 ml. of acetone, 5.7g. of triethylamine 4.0 g. of dimethylsulfamoyl chloride weresubstituted in the procedure of Example 21, there was obtained 292 mg.of 1-dimethylaminosulfonyl-2-amino-5(6)-butyrylbenzimidazole.

Analysis: C₁₃ H₁₈ N₄ O₃ S MW 310. Calcd: C, 50.31; H, 5.05; N, 18.05.Found: C, 49.93; H, 5.73; N, 17.84.

EXAMPLE 241-Dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminoethyl)benzimidazole

A solution of 423 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-acetylbenzimidazole and 300 mg. ofhydroxylamine hydrochloride in 60 ml. of methanol was refluxed for 17hours. The solution was concentrated on a steam bath to one-half itsvolume. To the solution was added 30 ml. of buffer solution (ph=7.00). Aprecipitate formed which was filtered and dried to yield 318 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(αhydroxyiminoethyl)benzimidazole.mp. 222°-225° C. (dec)

Analysis: C₁₁ H₁₅ N₅ O₃ S MW 297. Calcd: C, 44.43; H, 5.09; N, 23.55.Found: C, 44.64; H, 4.96; N, 23.21.

EXAMPLE 251-Dimethyaminosufonyl-2-amino-5(6)-(α-methoxyiminoethyl)benzimidazole

A solution of 141 mg. (0.5 mmole) of1-dimethylaminosufonyl-2-amino-5(6)-acetylbenzimidazole and 120 mg.(1.45 mmoles) of methoxyamine hydrochloride in 20 ml. of methanol wasrefluxed for 19 hours. The solution was concentrated on a steam bath toone-half its volume, then an equal volume of water was added. Thesolution was then concentrated until a solid started to appear. To thesolution was added 5 ml. of buffer solution (pH=7.00) which resulted inmore recrystallization. The solution was filtered, washed twice withwater and dried to yield 75 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-methoxyiminoethyl)benzimidazole,mp. 183°-185° C.

Analysis: C₁₂ H₁₇ N₅ O₃ S MW 311. Calcd: C, 46.29; H, 5.50, N, 22.49.Found: C, 46.50; H, 5.43; N, 22.22.

EXAMPLE 261-Dimethylaminosulfonyl-2-amino-5(6)-(α-thiocarbamylhydrazonoethyl)benzimidazole

Four hundred and twenty-three mg. of1-dimethylaminosulfonyl-2-amino-5(6)-acetylbenzimidazole, 300 mg. ofthiosemicarbazide, and 1.5 ml. of 1 N hydrochloric acid in 60 ml. ofmethanol was refluxed for 16.5 hours. The solution was concentrated on asteam bath and 30 ml. of buffer solution (pH=7.00) was added. Theproduct precipitated, filtered and dried to yield 360 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-thiocarbamylhydrazonoethyl)benzimidazole,mp. 230°-235° C. (dec)

Analysis: C₁₂ H₁₇ N₇ O₂ S₂ MW 355. Calcd: C, 40.55; H, 4.82; N, 27.59.Found: C, 40.22; H, 4.50; N, 27.27.

EXAMPLE 271-Dimethylaminosulfonyl-2-amino-5(6)-(α-thiocarbamylhydrazonopropyl)benzimidazole

One hundred forty eight mg. (0.5 mmoles) of1-dimethylaminosulfonyl-2-amino-5(6)-propionylbenzimidazole, 100 mg. (1mmole) of thiosemicarbazide, 20 ml. of methanol and 0.5 ml. of 1 Nhydrochloric acid was refluxed with stirring for 17.5 hours. Thesolution was concentrated to one-half its volume on a steam bath, anequal volume of water was added, and the solution was allowed to cool.On standing the product precipitated to yield 53 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-thiocarbamylhydrazonopropyl)benzimidazole.m/e 369.

EXAMPLE 281-Dimethylaminosulfonyl-2-formamido-5(6)-propionylbenzimidazole

Ten ml. of acetic anhydride were cooled to 0° C. in an ice bath. Fiveml. of 97-100 percent formic acid was slowly added. The solution waswarmed to 55° C. on a steam bath for 15 minutes, then cooled quickly and1 g. (0.0035 mole) of1-dimethylaminosulfonyl-2-amino-5(6)-propionylbenzimidazole was added.The slurry was cooled in an ice bath for 2 hours. The solution waspoured onto 50 g. of ice, filtered, washed with water, and dried toyield 1.1 g. of1-dimethylaminosulfonyl-2-formamido-5(6)-propionylbenzimidazole.

Analysis: C₁₃ H₁₆ N₄ O₄ S MW 324. Calcd: C, 48.14; H, 4.97; N, 17.27.Found: C, 48.37; H, 5.12; N, 17.05.

EXAMPLE 29 1-Dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole (A)2-Amino-5(6)-benzoylbenzimidazole

Three-hundred grams (1.52 mole) of 4-aminobenzophenone were added inportions to a stirred solution of 250 ml. of acetic anhydride in 250 ml.of benzene. The temperature of the mixture rose to about 70° C. Thereaction mixture was stirred overnight. The precipitated product wasfiltered, washed with benzene and dried. The yield of4-acetamidobenzophenone was 333.8 g. (91.5 percent yield), mp. 150°-152°C. (Lit. mp. 155° C., Chem. Abst. 55, 18651).

Twenty-three grams (0.1 mole) of 4-acetamidobenzophenone, 50 ml. ofacetic anhydride and 20 ml. of acetic acid were stirred together. Asolution of 90 percent nitric acid (15 ml.), 10 ml. of acetic acid and0.2 g. of urea was added dropwise to the benzophenone mixture. Thereaction mixture was maintained at a temperature of about 50° C. duringthe nitration. The mixture was stirred at ambient temperature whereuponthe mixture became very thick. The thick slurry was poured over ice andthe insoluble product was filtered to yield 17.7 g. (62.5 percent yield)of 4-acetamido-3-nitrobenzophenone.

Analysis: C₁₅ N₂ O₄ MW 284.27. Calcd: C, 63.38; H, 4.26; N, 9.85; O,22.51. Found: C, 63.57; H, 4.03; N, 9.90; O, 22.27.

Ten grams of 4-acetamido-3-nitrobenzophenone were added portionwise to40 ml. of sulfuric acid. The reaction temperature was moderated with awater bath. After stirring about 45 minutes the reaction mixture wascarefully poured over ice. The precipitated product was filtered toyield 4-amino-3-nitrobenzophenone.

Analysis: C₁₃ H₁₀ N₂ O₃ MW 242.23. Calcd: C, 64.46; H, 4.16; N, 11.56;O, 19.81. Found: C, 64.19; H, 4.00; N, 11.37; O, 19.72.

Fifty grams of 4-amino-3-nitrobenzophenone were hydrogenated at roomtemperature in 945 ml. of tetrahydrofuran with 15 g. of Raney nickel at2.74×10⁶ dynes/cm.². After 4 hours three equivalents of hydrogen wereabsorbed. The catalyst was filtered and the filtrate was evaporated invacuo to a solid residue. The residue was chromatographed over silicagel using ethyl acetate as eluant. Fractions 5-9 were combined to yield43.6 g. (100 percent yield) of 3,4-diaminobenzophenone.

Two-tenths mole, 42.4 g., of 3,4-diaminobenzophenone were dissolved in100 ml. of methanol and mixed into one liter of water. Two-tenths mole,21.8 g, of cyanogen bromide were added in portions to the reactionmixture with stirring. The reaction was continued overnight. Thereaction mixture was filtered and the filtrate was neutralized (pH 7.0)with concentrated ammonium hydroxide. The precipitated product wascollected, washed with water, and dried in a vacuum oven to yield 31 g.(68.5 percent) of 2-amino-5(6)-benzoylbenzimidazole.

Analysis: C₁₄ H₁₁ N₃ O MW 237.2. Calcd: C, 70.87; H, 4.67; N, 17.71.Found: C, 70.88; H, 4.60; N, 17.48.

(B) 1-Dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole

Twenty millimoles, 4.5 g., of 2-amino-5(6)-benzoylbenzimidazole weredissolved in 30 ml. of acetone and 4.0 g. of triethylamine. A solutionof 2.9 g. (20 mmole) of dimethylsulfamoyl chloride in 10 ml. of acetonewas added dropwise to the reaction mixture. The mixture was heated atreflux overnight. The reaction mixture was poured into 400 ml. of water.The product was extracted with chloroform. The extract was washed withwater, dried (Na₂ SO₄) and evaporated in vacuo to a residue. The residuewas crystallized from ethyl to acetate to yield 1.06 g. of1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole, mp. 206°-208° C.

Analysis: C₁₆ H₁₆ N₄ O₃ S MW 344. Calcd: C, 55.82; H, 4.65; N, 16.28.Found: C, 56.27; H, 4.80; N, 15.95.

EXAMPLE 30 1-Isopropylsulfonyl-2-amino-6-benzoylbenzimidazole

Thirty g. (0.126 mole) of 2-amino-5(6)-benzoylbenzimidazole, 250 ml. ofdimethoxyethane, and 6.3 g. (0.13 mole) of sodium hydride (50 percent inmineral oil) were stirred for one hour. To the mixture was added 19 g.of isopropylsulfonyl chloride in 20 ml. of dimethoxyethane. The mixturewas stirred for 16 hours at room temperature, refluxed for 2 hours,cooled, concentrated under vacuum, dissolved in 1500 ml. of ethylacetate, washed with water, dried, and concentrated by boiling to 200ml. When the solution cooled a precipitate formed which was filtered,and washed with diethyl ether to yield 11.1 g. of1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole.

Analysis: C₁₇ H₁₇ N₃ O₃ S MW 343. Calcd: C, 59.46; H, 4.99; N, 12.24.Found: C, 59.20; H, 5.03; N, 12.03.

EXAMPLE 31 1-Dimethylaminosulfonyl-2-formamido-5(6)-benzoylbenzimidazole

Ten ml. of acetic anhydride was added to 5 ml. of 97-100 percent formicacid. The solution was stirred and heated to 50°-55° C. for 15 minutes,then cooled to 0° C. in an ice bath. To the solution was added 1.0 g. of1-dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole and stirredfor 2 hours. The solution was then poured over ice, extracted twice withchloroform, washed the extracts once with water and once with saturatedsodium chloride, filtered and evaporated to yield 900 mg. of oil. Theoil was then dissolved in methanol and dried to yield 800 mg. of1-dimethylaminosulfonyl-2-formamido-5(6)-benzoylbenzimidazole. m/e 372.

EXAMPLE 32 1-Dimethylaminosulfonyl-2-acetamido-5(6)-benzoylbenzimidazole

A mixture of 1.0 g. of1-dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole, 4 ml. ofacetic anhydride and 400 mg. of anhydrous sodium acetate were heated to50° C. for 10 minutes. The mixture was stirred, 60 ml. of water wasadded, and the mixture stood for 16 hours. The solution was extractedthree times with chloroform, washed three times with water, washed oncewith saturated sodium chloride and dried to give 1.0 g. of1-dimethylaminosulfonyl-2-acetamido-5(6)-benzoylbenzimidazole. m/e 386.

EXAMPLE 331-Dimethylaminosulfonyl-2-amino-5(6)-p-chlorobenzoylbenzimidazole

When the procedure of Example 30 was repeated using 1.1 g. of2-amino-5(6)-p-chlorobenzoylbenzimidazole and 576 mg. ofdimethylsulfamoyl chloride as starting materials, there was obtained1-dimethylaminosulfonyl-2-amino-5(6)-p-chlorobenzoylbenzimidazole. m/e378.

EXAMPLE 341-Dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole

One hundred seventy two milligrams of1-dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole, 100 mg. ofhydroxylamine hydrochloride and 20 ml. of methanol were refluxed for 16hours. The reaction mixture was concentrated to one-half the originalvolume by heating on the steam bath. Ten milliliters of buffer (pH=7.0)were added to the mixture. The product precipitated and was filtered toyield 116 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,mp. 180°-183° C.

Analysis: C₁₆ H₁₇ N₅ O₃ S MW 359. Calcd: C, 53.47; H, 4.77; N, 19.49.Found: C, 53.42; H, 4.60; N, 19.17.

EXAMPLE 351-Isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole

A mixture of 1.7 g. (0.005 mole) of1-isopropylsulfonyl-2-amino-5(6)-benzoylbenzimidazole, 1 g. ofhydroxylamine hydrochloride, and 200 ml. of methanol were refluxed for18 hours. The reaction mixture was concentrated to one-half the originalvolume by heating on the steam bath. One hundred ml. of buffer (pH=7.0)were added to the mixture and the mixture was allowed to cool. Theproduct precipitated and was filtered to yield 1.2 g. of1-isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole.m/e 358.

Analysis: C₁₇ H₁₈ N₄ O₃ S MW 358. Calcd: C, 56.97; H, 5.06; N, 15.63.Found: C, 56.67; H, 5.34; N, 15.25.

EXAMPLE 361-Dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyimino-p-chlorobenzyl)benzimidazole

When 1.1 g. (3 mmoles) of1-dimethylaminosulfonyl-2-amino-(5(6)-p-chlorobenzoylbenzimidazole, 600mg. of hydroxylamine hydrochloride and 120 ml. of methanol aresubstituted in the procedure of Example 34, there was obtained 1.5 g. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyimino-p-chlorobenzyl)benzimidazole.m/e 378.

EXAMPLE 371-Dimethylaminosulfonyl-2-amino-5(6)-(α-methoxyiminobenzyl)benzimidazole

When 688 mg. (2 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole, 500 mg. ofmethoxyamine hydrochloride and 80 ml. of methanol were substituted inthe procedure of Example 25, there was obtained 530 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-methoxyiminobenzyl)benzimidazole.

Analysis: C₁₇ H₁₉ N₅ O₃ S MW 373. Calcd: C, 54.68; H, 5.13; N, 18.75.Found: C, 54.66; H, 5.06; N, 18.92.

EXAMPLE 381-Isopropylsulfonyl-2-amino-5(6)-(α-methoxyiminobenzyl)benzimidazole

When 1.7 g. of 1-isopropylsulfonyl-2-amino-5(6)-benzoylbenzimidazole,1.2 g. of methoxyamine hydrochloride, and 200 ml. of methanol weresubstituted in the procedure of Example 25, there was obtained an oil.The oil was treated with a saturated solution of sodium chloride,extracted with ethyl acetate and dried. After extraction several timeswith benzene there was obtained 1 g. of1-isopropylsulfonyl-2-amino-5(6)-(α-methoxyiminobenzyl)benzimidazole, asa solid foam.

Analysis: C₁₈ H₂₀ N₄ O₃ S MW 372. Calcd: C, 58.05; H, 5.41; N, 15.04.Found: C, 57.98; H, 5.72; N, 14.99.

EXAMPLE 391-Dimethylaminosulfonyl-2-amino-5(6)-(α-ethoxyiminobenzyl)benzimidazole

To 15 ml. of absolute ethanol was added 718 mg. (2 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazolewith stirring. To the solution was added 120 mg. (2.2 mmole) of sodiummethoxide, then 552 mg. (3.54 mmole) of ethyl iodide. The solution wasrefluxed for 21/2 hours, cooled, and evaporated to one-half the volume.The solution was poured into water, extracted twice with chloroform,washed twice with saturated sodium chloride, dried and filtered to yield227 mg., as a white foamy solid,1-dimethylaminosulfonyl-2-amino-5(6)-(α-ethoxyiminobenzyl)benzimidazole.

Analysis: C₁₈ H₂₁ N₅ O₃ S MW 387. Calcd: C, 55.80; H, 5.46; N, 18.08.Found: C, 56.03; H, 5.33; N, 18.27.

EXAMPLE 401-Dimethylaminosulfonyl-2-amino-5(6)-(α-propoxyiminobenzyl)benzimidazole

When 718 mg. (2 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,15 ml. of methanol, 120 mg. (2.2 mmoles) of sodium methoxide and 600 mg.(3.54 mmole) of 1-iodopropane were substituted in the procedure ofExample 39, there was obtained 248 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-propoxyiminobenzyl)benzimidazole,as a white solid.

Analysis: C₁₉ H₂₃ N₅ O₃ S MW 401. Calcd: C, 56.84; H, 5.77; N, 17.44.Found: C, 56.63; H, 5.54; N, 17.60.

EXAMPLE 411-Dimethylaminosulfonyl-2-amino-5(6)-(α-benzyloxyiminobenzyl)benzimidazole

A solution of 172 mg. (0.5 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole, 230 mg. (1.45mmoles) of benzyloxyamine hydrochloride and 20 ml. of methanol wasrefluxed for 191/2 hours. The solution was then treated according to theprocedure of Example 34 to yield 161 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-benzyloxyiminobenzyl)benzimidazole.

Analysis: C₂₃ H₂₃ N₅ O₃ S MW 449. Calcd: C, 61.45; H, 5.16; N, 15.58.Found: C, 61.51; H, 5.20; N, 15.37.

EXAMPLE 421-Dimethylaminosulfonyl-2-amino-5(6)-(α-acetoxyiminobenzyl)benzimidazole

To a solution of 359 mg. (1 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazolein 4.4 ml. of dimethylformamide was added 54 mg. (1 mmole) of sodiummethoxide with stirring. One hundred and two mg. (1 mmole) of aceticanhydride was added to the solution and the solution stirred for 5minutes. To the solution was added 26.5 ml. of water and 25 ml. ofbuffer (pH=7.00). The solution was stirred one hour, then filtered toyield 320 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-acetoxyiminobenzyl)benzimidazole.mp. 137°-139° C.

Analysis: C₁₈ H₁₉ N₅ O₄ S MW 401. Calcd: C, 53.85; H, 4.77; N, 17.45.Found: C, 53.58; H, 4.59; N, 17.80.

EXAMPLE 431-Isopropylsulfonyl-2-amino-5(6)-(α-acetoxyiminobenzyl)benzimidazole

When 1 g. (0.003 mole) of1-isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,162 mg. (0.003 mole) of sodium methoxide, 10 ml. of dimethylformamide,and 0.3 ml. of acetic anhydride were substituted in the procedure ofExample 40, there was obtained 900 mg. of1-isopropylsulfonyl-2-amino-5(6)-(α-acetoxyiminobenzyl)benzimidazole

Analysis: C₁₉ H₂₀ N₄ O₄ S MW 400. Calcd: C, 56.99; H, 5.03; N, 13.99.Found: C, 57.20; H, 5.24; N, 13.86.

EXAMPLE 441-Dimethylaminosulfonyl-2-acetamido-5(6)-(α-acetoxyiminobenzyl)benzimidazole

One hundred and eighty-one mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,2 ml. of pyridine, and 2 ml. of acetic anhydride were mixed and allowedto stand at room temperature for 171/2 hours. The solution was thenevaporated to dryness, extracted with methanol, and evaporated to yield132 mg. of1-dimethylaminosulfonyl-2-acetamido-5(6)-(α-acetoxyiminobenzyl)benzimidazole.mp. 162°-165° C. (dec)

Analysis: C₂₉ H₂₁ N₅ O₅ S MW 443. Calcd: C, 54.17; H, 4.77; N, 15.79.Found: C, 54.03; H, 4.89; N, 15.85.

EXAMPLE 451-Dimethylaminosulfonyl-2-amino-5(6)-(α-propionyloxyiminobenzyl)benzimidazole

When 359 mg. (1 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,4.4 ml. of dimethylformamide, 54 mg. (1 mmole) of sodium methoxide, and130 mg. of propionic anhydride were substituted in the procedure ofExample 42, there was obtained 367 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-propionyloxyiminobenzyl)benzimidazole.m/e 415.

EXAMPLE 461-Dimethylaminosulfonyl-2-amino-5(6)-(α-butyryloxyiminobenzyl)benzimidazole

When 359 mg. (1 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,4.4 ml. of dimethylformamide, 54 mg. of sodium methoxide, and 158 mg. (1mmole) of butyric anhydride were substituted in the procedure of Example42, there was obtained 342 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-butyryloxyiminobenzyl)benzimidazole.

Analysis: C₂₀ H₂₃ N₅ O₄ S MW 429. Calcd: C, 55.93; H, 5.40; N, 16.31.Found: C, 54.05; H, 5.21; N, 17.13.

EXAMPLE 471-Dimethylaminosulfonyl-2-amino-5(6)-(α-benzoyloxyiminobenzyl)benzimidazole

When 539 mg. (1.5 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,6.6 ml. of dimethylformamide, 81 mg. (15 mmole) of sodium methoxide, and339 mg. (1.5 mmole) of benzoic anhydride were substituted in theprocedure of Example 42, there was obtained 600 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-benzoyloxyiminobenzyl)benzimidazole.m/e 463.

EXAMPLE 481-Dimethylaminosulfonyl-2-amino-5(6)-(α-methoxycarbonyloxyiminobenzyl)benzimidazole

To a solution of 359 mg. (1 mmole) of1-dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazolein 4 ml. of dimethylformamide was added 63 mg. (1.2 mmole) of sodiummethoxide. A solution of 100 mg. (1.1 mmole) of methoxycarbonyl chloridein 0.5 ml. of dimethylformamide was added to the reaction mixture. Themixture was stirred for 5 minutes, then 40 ml. of buffer (pH=7.00) wasadded. The mixture was stirred again for 5 minutes, filtered, washedwith water, and dried to yield 290 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-methoxycarbonyloxyiminobenzyl)benzimidazole.m/e 417.

EXAMPLE 491-Dimethylaminosulfonyl-2-amino-5(6)-thiocarbamylhydrazonobenzylbenzimidazole

One hundred and seventy-two mg. of1-dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole, 100 mg. ofthiosemicarbazide, and 0.5 ml. 1 N hydrochloric acid in 20 ml. ofmethanol were refluxed for 16 hours. The thiosemicarbazone productprecipitated upon cooling and was collected to yield 94 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-thiocarbamylhydrazonobenzylbenzimidazole.m/e 417.

EXAMPLE 501-Dimethylaminosulfonyl-2-amino-5(6)-(α-ethoxycarbonylhydrazonobenzyl)benzimidazole

To 300 ml. of boiling ethanol were added 3.2 g. (0.0093 mole) of1-dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole and 1 g.(0.0096 mole) of ethoxycarbonylhydrazine. The mixture was heated on asteam bath for 4 hours. One ml. of concentrated hydrochloric acid wasadded to the mixture, and then the mixture was heated for 10 hours. Thesolvent was removed under vacuum, 300 ml. of water was added. Thesolution stood 19 hours, was extracted with ethyl acetate, dried, andconcentrated under vacuum to yield 1.7 g. of1-dimethylaminosulfonyl-2-amino-5(6)-(α-ethoxycarbonylhydrazonobenzyl)benzimidazole,as a foam.

Analysis: C₁₉ H₂₂ H₆ O₄ S MW 430. Calcd: C, 53.01; H, 5.15; N, 19.52.Found: C, 52.82; H, 5.51; N, 18.44.

EXAMPLE 511-Isopropylsulfonyl-2-amino-5(6)-(α-ethoxycarbonylhydrazonobenzyl)benzimidazole

When the procedure of Example 50 was repeated using 3 g. (0.00875 mole)of 1-isopropylsulfonyl-2-amino-5(6)-benzoylbenzimidazole, 300 ml. ofabsolute ethanol, 1 g. (0.0096 mole) of ethoxycarbonylhydrazine, and 1ml. (0.01 mole) of concentrated hydrochloric acid, there was obtained2.4 g. of1-isopropylsulfonyl-2-amino-5(6)-(α-ethoxycarbonylhydrazonobenzyl)benzimidazole.m/e 429, 357, 343.

Analysis: C₂₀ H₂₃ N₅ O₄ S MW 429. Calcd: C, 55.93; H, 5.40; N, 16.31.Found: C, 55.96; H, 5.10; N, 16.57.

EXAMPLE 521-Isopropylsulfonyl-2-amino-5(6)-(α-carboxymethoxyiminobenzyl)benzimidazole

When the procedure of Example 50 was repeated using 1.7 g. (0.005 mole)of 1-isopropylsulfonyl-2-amino-5(6)-benzoylbenzimidazole, 200 ml. ofmethanol, 1.1 g. of carboxymethoxyamine hemihydrochloride, and 0.3 ml.(0.003 mole) of concentrated hydrochloric acid, there was obtained 2 g.of1-isopropylsulfonyl-2-amino-5(6)-(α-carboxymethoxyiminobenzyl)benzimidazole.pK_(a) 6.91 in 66 percent dimethylformamide/water.

EXAMPLE 531-Dimethylaminosulfonyl-2-amino-5(6)-[1(2)-methyltetrazol-5-yl]benzimidazole(A) 5-(3-Nitro-4-acetamidophenyl)tetrazole

A solution of 10.3 g. (0.05 mole) of 3-nitro-4-acetamidobenzonitrile,3.5 g. of sodium azide and 3.9 g. of ammonium chloride 100 ml. ofdimethylformamide was refluxed for 16 hours. The cooled reaction mixturewas poured into 500 ml. of 1 N hydrochloric acid and diluted with 300ml. of water. The yellow product precipitated and was collected to yield10 g. (81 percent) of 5-(3-nitro-4-acetamidophenyl)tetrazole. mp.210°-213° C.° (dec)

(B) 1(2)-Methyl-5-(3-nitro-4-acetamidophenyl)tetrazole

5-(3-Nitro-4-acetamidophenyl)tetrazole, 31.7 g. (0.13 mole), wasdissolved in 200 ml. of acetone. Twenty three milliliters (0.17 mole) oftriethylamine was added to the reaction mixture. The mixture was stirreduntil it became homogeneous. Thirty milliliters of methyl iodide wereadded followed by the addition of another 20 ml. of methyl iodide after12 hours at room temperature. The reaction was continued another fourhours. The precipitated product was collected and the filtrate wasconcentrated to one fourth the original volume in vacuo. The total yieldwas 20 g. (59 percent) of an isomeric mixture of1(2)-methyl-5-(3-nitro-4-acetamidophenyl)tetrazole.

Analysis: C₁₀ H₁₀ N₆ O₃ MW 262. Calcd: C, 45.80; H, 3.84; N, 32.05.Found: C, 45.64; H, 3.84; N, 32.18.

(C) 1(2l )-Methyl-5-(3-nitro-4-aminophenyl)tetrazole

Two grams of 1(2)-methyl-5-(3-nitro-4-acetamidophenyl)tetrazole wereadded to 20 ml. of concentrated sulfuric acid at room temperature. Thetetrazole slowly went into solution and the mixture was stirred forabout 2 hours. The acid mixture was poured carefully into 200 ml. ofcold water. The precipitated product was collected to yield 1.6 g. (95percent) of 1(2)-methyl-5-(3-nitro-4-amino)tetrazole, mp. about 200° C.

Analysis: C₈ H₈ N₆ O₂ MW 220. Calcd: C, 43.64; H, 3.66; N, 38.17. Found:C, 43.37; H, 3.70; N, 37.89.

(D) 1(2)-Methyl-5-(3,4-diaminophenyl)tetrazole

Fourteen grams of 1(2)-methyl-5(3-nitro-4-aminophenyl)tetrazole werehydrogenated at 4.13×10⁶ dynes/cm.² with 1 g. of palladium-on-carbon in135 ml. of ethyl acetate and 350 ml. of absolute ethanol. After 2 hoursthree equivalents of hydrogen were absorbed. The catalyst was filteredand the filtrate was evaporated in vacuo to yield 12 g. (98 percent) of1(2)-methyl-5-(3,4-diaminophenyl)tetrazole.

Analysis: C₈ H₁₀ N₆ MW 190. Calcd: C, 50.52; H, 5.30; N, 44.18. Found:C, 50.79; H, 5.57; N, 43.95.

(E) 1(2)-Methyl-5-(2-aminobenzimidazol-5(6)-yl)tetrazole

Cyanogen bromide, 3.2 g. (0.03 mole), was added to a slurry of 5.7 g.(0.03 mole) of 1(2)-methyl-5-(3,4-diaminophenyl)tetrazole in 300 ml. ofwater and 30 ml. of methanol. The mixture was stirred for 12 hours andfiltered. The filtrate was neutralized with potassium carbonate. Theprecipitated product was collected to yield 5.7 g. (88 percent) of1(2)-methyl-5-(2-aminobenzimidazol-5(6)-yl)tetrazole.

Analysis: C₉ H₉ N₇ MW 215. Calcd: C, 50.23; H, 4.22; N, 45.56. Found: C,49.56; H, 4.34; N, 44.06.

(F)1-Dimethylaminosulfonyl-2-amino-5(6)-[1(2)-Methyltetrazol-5-yl]benzimidazole

1(2)-Methyl-5-(2-aminobenzimidazol-5(6)-yl)tetrazole, 2.2 g. (0.01mole), 50 ml. of acetone, 1.5 ml. of triethylamine, and 1 g. ofdimethylsulfamoyl chloride were refluxed for 18 hours. After coolingunreacted starting material was filtered and the filtrate was evaporatedto a residue in vacuo. The red oily residue was triturated with methanolto yield 300 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-[1(2)-methyltetrazol-5-yl]benzimidazole.

Analysis: C₁₁ H₁₄ N₈ O₂ S MW 322. Calcd: C, 40.99; H, 4.38; N, 34.76.Found: C, 40.72; H, 4.38; N, 34.51.

The following intermediates and final product were prepared by themethods of Example 53. Alkylation of the tetrazole moiety with isopropyliodide gave only a single isomer.

EXAMPLE 54

(A) 1-Isopropyl-5-(3-nitro-4-aminophenyl)tetrazole, mp. 126°-128° C.,yield 71 percent.

Analysis: C₁₀ H₁₂ N₆ O₂ MW 200. Calcd: C, 48.38; H, 4.87; N, 33.85.Found: C, 48.19; H, 4.93; N, 33.61.

(B) 1-Isopropyl-5-(3,4-diaminophenyl)tetrazole, yield 70 percent.

Analysis: C₁₀ H₁₄ N₆ MW 218. Calcd: C, 55.03; H, 6.47; N, 38.50. Found:C, 55.23; H, 6.27; N, 38.73.

(C) 1-Isopropyl-5-[2-aminobenzimidazol-5(6)-yl]tetrazole, mp. 232°-233°C., yield 7.3 g. (86 percent)

Analysis: C₁₁ H₁₃ N₇ MW 243. Calcd: C, 54.31; H, 5.39; N, 40.30. Found:C, 54.56; H, 5.54; N, 40.53.

(D)1-Dimethylaminosulfonyl-2-amino-5(6)-(1-isopropyltetrazol-5-yl)benzimidazole,mp. 211°-213° C.

Analysis: C₁₃ H₁₈ N₈ O₂ S MW 350. Calcd: C, 44.56; H, 5.18; N, 31.98.Found: C, 44.83; H, 5.33; N, 31.77.

EXAMPLE 551-Dimethylaminosulfonyl-2-Amino-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazole(A) 1-Dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide.

Three grams of ethyl1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate, 50 ml. ofmethanol and 6 ml. of hydrazine hydrate were refluxed for about 100hours. The hydrazide product crystallized out of solution during thereaction. The hot reaction mixture was filtered to yield 200 mg. of1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxylic acidhydrazide, mp. about 229°-230° C. (dec), confirmed by nuclear magneticresonance spectrum.

Analysis: C₁₀ H₁₄ N₆ O₃ S MW 298. Calcd: C, 40.30; H, 4.70; N, 28.20.Found: C, 40.21; H, 4.54; N, 28.33.

Upon cooling the filtrate yielded a solid which was collected. The solidwas a mixture of isomeric acid hydrazides. The subsequent filtratesyielded two crops of crystals upon concentrating and cooling to give acombined yield of 350 mg. of1-dimethylaminosulfonyl-2-amino-6-benzimidazole carboxylic acidhydrazide hydrate, mp. about 205°-206° C., confirmed by NMR.

Analysis: C₁₀ H₁₄ N₆ O₃ S.H₂ O MW 316. Calcd: C, 37.97; H, 5.06; N,26.58. Found: C, 38.40; H, 4.41; N, 26.15.

(B)1-Dimethylaminosulfonyl-2-(ethoxymethyleneamino-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazole.

Three grams (0.01 mole) of1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide and 100 ml. of ethyl orthoformate were heated at reflux for 24hours with the use of a Dean-Stark trap. The reaction mixture wasevaporated to dryness in vacuo. The residue was dissolved in ethylacetate and the product was crystallized by concentrating and cooling toyield 580 mg. of1-dimethylaminosulfonyl-2-(ethoxymethyleneamino)-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazole.

Analysis: C₁₄ H₁₆ N₆ O₄ S MW 364. Calcd: C, 46.15; H, 4.40; N, 23.08.Found: C, 46.19; H, 4.38; N, 22.64.

(C)1-Dimethylaminosulfonyl-2-amino-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazole.

Five hundred and eithty milligrams of1-dimethylaminosulfonyl-2-(ethoxymethyleneamino)-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazolewas stirred for 1 hour at room temperature in 10 ml. of 1 N hydrochloricacid. The reaction mixture was filtered to yield 230 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazolehydrochloride, mp. 200° C. (dec)

Analysis: C₁₁ H₁₂ N₆ O₃ S.HCl MW 344.5. Calcd: C, 38.32; H, 3.80; N,24.38. Found: C, 38.54; H, 4.07; N, 24.61.

The acid filtrate from (C) above was treated with sodium carbonate untilthe solution was basic to litmus. A solid precipitated from the basicsolution. The precipitated solid was filtered to yield 120 mg. of1-dimethylaminosulfonyl-2-amino-5(6)-(1,3,4-oxadiazol-2-yl)benzimidazole,mp. 230°-231° C. dec.

Analysis: C₁₁ H₁₂ N₆ O₃ S MW 308. Calcd: C, 42.85; H, 4.19; N, 27.03.Found: C, 42.61; H, 3.92; N, 27.26.

EXAMPLE 56 1-Cyclohexylsulfonyl-2-amino-6-benzoylbenzimidazole

When the procedure of Example 29 was repeated using 475 g. of2-amino-5(6)-benzoylbenzimidazole, 2.5 moles of sodium hydride, and 365g. of cyclohexylsulfonyl chloride, there was obtained 120 g. of1-cyclohexylsulfonyl-2-amino-6-benzoylbenzimidazole. mp. 210°-213° C.(dec)

Analysis: C₂₀ H₂₁ N₃ O₃ S MW 383. Calcd: C, 62.64; H, 5.52; N, 10.96.Found: C, 62.43; H, 5.27; N, 10.51.

EXAMPLE 57 1-(Thien-2-ylsulfonyl)-2-amino-5(6)-benzoylbenzimidazole

When the procedure of Example 29 was repeated using 26.4 g. (1.1 mole)of sodium hydride, 260 g. (1.1 mole) of2-amino-5(6)-benzoylbenzimidazole, and 200 g. of thiophenylsulfonylchloride, there was obtained1-(thien-2-ylsulfonyl)-2-amino-5(6)-benzoylbenzimidazole. m/e 351.

EXAMPLE 58 1-Dimethylaminosulfonyl-2-amino-5(6)-hydroxybenzimidazole (A)2-Amino-5(6)-methoxybenzimidazole

Thirty three grams (0.24 mole) of 4-methoxy-o-phenylenediamine wasstirred in 625 ml. of water. Twenty-five (0.24 mole) of cyanogen bromidein 30 ml. of methanol was added slowly to the aqueous reaction mixture.An additional 35 ml. of methanol was added. The reaction was continuedat room temperature for about 17 hours. The reaction mixture wasfiltered and the filtrate was basified with a solution of 25 g. (0.25mole) of potassium carbonate in 150 ml. of water. The mixture wasallowed to stand until crystallization of the product was complete. Theproduct was collected and recrystallized from 600 ml. of ethyl acetateto yield 10 g. of 2-amino-5(6)-methoxybenzimidazole.

(B) 2-Amino-5(6)-hydroxybenzimidazole

One and a half grams of 2-amino-5(6)-methoxybenzimidazole and 17 ml. of48 percent hydrogen bromide were refluxed with stirring for one hour.The product crystallized upon refrigeration overnight. The product wascollected to yield 0.40 g. of 2-amino-5(6)-hydroxybenzimidazolehydrobromide.

(C) 1- Dimethylaminosulfonyl-2-amino-5(6)-hydroxybenzimidazole

Twenty millimoles, 4.6 g., of 2-amino-5(6)-hydroxybenzimidazole, 20 ml.of acetone, 5.5 ml. (40 mmoles) of triethylamine, and 2.9 g. (20 mmoles)of dimethyl sulfamoyl chloride in 5 ml. of acetone were refluxed forabout 20 hours. The reaction mixture was poured into 300 ml. of water.The aqueous mixture was extracted with ethyl acetate. The ethyl acetateextract was washed successively with water and saturated sodium chloridesolution. After drying the ethyl acetate solution was evaporated invacuo to give 3.0 g. of gummy residue. The residue was taken up in hotethyl acetate and the product was allowed to crystallize. The productwas collected to yield 523 mg. of the 6-isomer,1-Dimethylaminosulfonyl-2-amino-6-hydroxybenzimidazole, mp. 217°-219° C.An analytical sample was prepared, mp. 227°-228° C.

Analysis C₉ H₁₂ N₄ O₃ S MW 256. Calcd: C, 42.18; H, 4.72; N, 21.86; S,12.51. Found: C, 42.35; H, 4.80; N, 21.80; S, 12.34.

The mother liquors form the crystallization of the 6-isomer wereevaporated to yield 1.5 g. of solid residue. The material waschromatographed using 150 g. of Woelm silica gel packed with 1:1toluene-ethyl acetate, The product was eluted with toluene-ethylacetate, 300 ml. (1:1), 300 ml. (1:2) and 400 ml. (1:3) and ethylacetate to end. Ten milliliter fractions were collected. Product startedcoming off at fraction 129. Fractions 214 to 228 were combined toprovide 39 mg. of the 5-isomer,1-dimethylaminosulfonyl-2-amino-5-hydroxybenzimidazole.

EXAMPLE 59 1-Dimethylaminosulfonyl-2-amino-5(6)-acetoxybenzimidazole

One millimole, 257 mg., of1-dimethylaminosulfonyl-2-amino-5(6)-hydroxybenzimidazole was dissolvedin 3 ml. of dimethylformamide (DMF). Sixty milligrams (1.1 mole) ofsodium methylate were added to the reaction mixture. After about oneminute, a solution of 107 mg. of acetic anhydride in 1 ml. of DMF wasadded. Within 5 minutes, 18 ml. of water and 17 ml. of pH 7.00 bufferwere added to the reaction mixture. The product began to precipitateafter a few minutes. After 30 minutes the product was collected to yield170 mg. (57 percent) of1-dimethylaminosulfonyl-2-amino-5(6)-acetoxybenzimidazole as an isomericmixture.

Analysis: C₁₁ H₁₄ N₄ O₄ S MW 298. Calcd: C, 44.29; H, 4.73; N, 18.78.Found: C, 44.13; H, 4.83; N, 18.72.

The following esters were prepared by the method of Example 59 usingpropionic, butyric or benzoic anhydride instead of acetic anhydride.

1-Dimethylaminosulfonyl-2-amino-5(6)-propionyloxybenzimidazole

Analysis C₁₂ H₁₄ O₄ S MW 310. Calcd: C, 46.14; H, 5.16; N, 17.94. Found:C, 45.87; H, 5.02; N, 17.76.

1-Dimethylaminosulfonyl-2-amino-5(6)-butyryloxybenzimidazole

Analysis C₁₃ H₁₆ N₄ O₄ S MW 324. Calcd: C, 47.84; H, 5.56; N, 17.17.Found: C, 47.61; H, 5.33; N, 17.13.

1-Dimethylaminosulfonyl-2-amino-5(6)-benzoyloxybenzimidazole

Analysis C₁₆ H₁₄ N₄ O₄ S MW 368. Calcd: C, 53.32; H, 4.48; N, 15.55.Found: C, 53.04; H, 4.41; N, 15.26.

EXAMPLE 60 1-Dimethylaminosulfonyl-2-acetamido-6-hydroxybenzimidazole

1-Dimethylaminosulfonyl-2-acetamido-6-acetoxybenzimidazole, 170 mg.(0.50 mmole), was dissolved in 3.0 ml. of dimethylformamide and 2.0 ml.of pH 10.0 buffer was added. One-half milliter of three percent hydrogenperoxide was added to the reaction mixture. The reaction mixture wasallowed to stir at room temperature for about 10 minutes. The mixturewas poured into 50 ml. of 0.1 N hydrochloric acid. The acid mixture wasextracted with chloroform. The extract was washed successively withwater and saturated sodium chloride solution. The chloroform solutionwas dried and evaporated in vacuo to yield 102 mg. of1-dimethylaminosulfonyl-2-acetamido-6-hydroxybenzimidazole, mp.175°-176° C., after crystallization

Analysis C₁₁ H₁₄ N₄ O₄ S MW 298. Calcd: C, 43.29; H, 4.73; N, 18.78; S,10.75. Found: C, 44.24; H, 4.55; N, 18.51; S, 10.65.

EXAMPLE 61 1-Dimethylaminosulfonyl-2-acetamido-6-acetoxybenzimidazole

1-Dimethylaminosulfonyl-2-amino-6-hydroxybenzimidazole, 250 mg., 1 ml.of acetic anhydride and 0.10 mg. of sodium acetate (anhydrous) werewarmed (hot water) for about ten minutes. Fifteen milliliters of waterwere added to the mixture with stirring. Product crystallized afterone-half hour. The material was collected to yield 226 mg. (66 percent)of 1-dimethylaminosulfonyl-2-acetamido-6-acetoxybenzimidazole, mp.164°-166° C. (ethyl acetate)

Analysis C₁₃ H₁₆ N₄ O₅ S MW 340. Calcd: C, 45.88; H, 4.74; N, 16.46; S,9.42. Found: C, 45.93; H, 4.70; N, 16.26; S, 9.62.

EXAMPLE 621-Isopropylsulfonyl-2-amino-5(6)-(n-propionyloxyiminobenzyl)benzimidazole

When 1 g. (0.003 mole) of1-isopropylsulfonyl-2-amino-5-(6)-(α-hydroxyiminobenzyl)benzimidazole,162 mg. (0.003 mole) of sodium methoxide, 10 ml. of dimethylformamide,and 0.3 ml. of propionic anhydride were substituted in the procedure ofExample 42, there was obtained 860 mg. of1-isopropylsulfonyl-2-amino-5(6)-(n-propionyloxyiminobenzyl)benzimidazole

Analysis C₂₀ H₂₂ N₄ O₄ S MW 414. Calcd: C, 57.96; H, 5.35; N, 13.52.Found: C, 58.20; H, 5.36; N, 13.75.

EXAMPLE 631-Isopropylsulfonyl-2-amino-5(6)-(n-butyryloxyiminobenzyl)benzimidazole

When 1 g. (0.003 mole) of1-isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,162 mg. (0.003 mole) of sodium methoxide, 10 ml. of dimethylformamide,and 0.5 ml. of butyric anhydride were substituted in the procedure ofExample 42, there was obtained 900 mg. of1-isopropylsulfonyl-2-amino-5(6)-(n-butyryloxyiminobenzyl)benzimidazole.

Analysis C₂₁ H₂₄ N₄ O₄ S MW 428. Calcd: C, 58.86; H, 5.65; N, 13.08.Found: C, 58.64; H, 5.44; N, 13.35.

EXAMPLE 641-Isopropylsulfonyl-2-amino-5(6)-(n-pentanoyloxyiminobenzyl)benzimidazole

To a solution of 1 g. (0.003 mole) of1-isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole in10 ml. of dimethylformamide was added 162 mg. (0.003 mole) of sodiummethoxide with stirring. The solution turned dark in color. Valericanhydride, 0.6 ml. (0.003 mole, d=0.924), was added to the solution andthe solution stirred for 2 hours. The solution was poured with stirringinto 100 ml. of buffer (pH=7.00) and 100 ml. of water. The product wascollected by filtration, washed with water, dried, dissolved in 10 ml.of chloroform, diluted with isopropyl ether on a steam bath to 50 ml.,boiled to concentrate the volume, cooled to 0° C., and filtered to yield700 mg., as an amorphous yellow foam,1-isopropylsulfonyl-2-amino-5(6)-(n-pentanoyloxyiminobenzyl)benzimidazole.

Analysis C₂₂ H₂₆ N₄ O₄ S MW 442. Calcd: C, 59.71; H, 5.92; N, 12.66.Found: C, 59.58; H, 6.16; N, 12.65.

EXAMPLE 651-Isopropylsulfonyl-2-amino-5(6)-(pivaloyloxyiminobenzyl)benzimidazole

When 1 g. (0.003 mole) of1-isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,0.43 ml. (0.003 ml.) of triethylamine, 10 ml. of chloroform, and 0.36ml. of pivaloyl chloride were substituted in the procedure of Example42, and followed by trituration with methanol/isopropyl ether, there wasobtained 860 mg. of1-isopropylsulfonyl-2-amino-5(6)-pivaloyloxyiminobenzyl)benzimidazole.

Analysis C₂₂ H₂₆ N₄ O₄ S MW 442. Calcd: C, 59.71; H, 5.92; N, 12.66.Found: C, 59.47; H, 5.78; N, 12.44.

EXAMPLE 661-Isopropylsulfonyl-2-amino-5(6)-(3-methoxycarbonylpropionyloxyiminobenzyl)benzimidazole

To a solution of 1 g. (0.003 mole) of1-isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole in10 ml. of chloroform was added 0.43 ml. (0.003 mole) of triethylaminewith stirring. To the solution was added 5 ml. of chloroform with 0.38ml. (0.003 mole) of 3-carbomethoxypropionyl chloride with stirring. Thesolution stood overnight, was extracted twice with water, dried,filtered, concentrated under vacuum, taken up in benzene, andconcentrated under vacuum to yield 950 mg. of1-isopropylsulfonyl-2-amino-5(6)-(3-methoxycarbonylpropionyloxyiminobenzyl)benzimidazole.

Analysis C₂₂ H₂₄ N₄ O₆ S MW 472. Calcd: C, 55.92; H, 5.12; N, 11.86.Found: C, 56.02; H, 5.09; N, 11.65.

EXAMPLE 671-Isopropylsulfonyl-2-amino-5(6)-[2-(p-nitrobenzyloxycarbonyl)ethylcarbonyloxyiminobenzyl]benzimidazole

When 1.8 g. (0.005 mole) of1-isopropylsulfonyl-2-amino-(α-hydroxyiminobenzyl)benzimidazole in 20ml. of chloroform, 0.8 ml. of triethylamine, and 1.2 g. ofp-nitrobenzyloxycarbonylpropionyl chloride in 10 ml. of chloroform weresubstituted in the procedure of Example 66, there was obtained 2 g. of1-isopropylsulfonyl-2-amino-5(6)-[2-(p-nitrobenzyloxycarbonyl)ethylcarbonyloxyiminobenzyl]benzimidazole.

Analysis C₂₈ H₂₇ N₅ O₈ S MW 593. Calcd: C, 56.75; H, 4.42; N, 11.82.Found: C, 56.53; H, 4.69; N, 11.54.

EXAMPLE 681-Isopropylsulfonyl-2-amino-5(6)-(benzyloxycarbonylaminomethylcarbonyloxyiminobenzyl)benzimidazole

One gram (0.005 mole) of benzyloxycarbonylaminomethylcarboxylic acid in20 ml. of benzene was stirred and 0.9 ml. (0.01 mole) of oxalyl chlorideand 1 drop of pyridine was added. The solution was stirred for 1 hour,warmed on a steam bath, concentrated under vacuum, taken up in benzene,concentrated under vacuum until dry. The residue was dissolved in 10 ml.of chloroform and added to 1.8 g. (0.005 mole) of1-isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole and0.8 ml. (0.005 mole) of triethylamine in 20 ml. chloroform. The solutionstood at room temperature overnight. The solution was washed twice withwater, buffer (pH=4), buffer (pH=10), dried, and concentrated to aresidue. The residue was recrystallized from methanol, diluted withdiisopropyl ether, and filtered to yield 840 mg. of1-isopropylsulfonyl-2-amino-5(6)-(benzyloxycarbonylaminomethylcarbonyloxyiminobenzyl)benzimidazole,m/e 292 (loss of isopropylsulfonyl group and benzyloxycarbonylaminogroup).

EXAMPLE 691-Isopropylsulfonyl-2-amino-5(6)-(phthalimidomethylcarbonyloxyiminobenzyl)benzimidazole

When 1 g. (0.005 mole) of phthalimidomethylcarboxylic acid, 0.9 ml. (1.3g., 0.01 mole) of oxalyl chloride in 15 ml. of benzene, 1 drop ofpyridine, 1.8 g. (0.005 mole) of1-isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,and 0.8 ml. (0.005 mole) of triethylamine were substituted in theprocedure of Example 61, there was obtained 2.3 g. of1-isopropylsulfonyl-2-amino-5(6)-(phthalimidomethylcarbonyloxyiminobenzyl)benzimidazole.m/e 545.

EXAMPLE 701-Isopropylsulfonyl-2-amino-5(6)-[2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxyiminobenzyl]benzimidazole

When 0.9 g. (0.003 mole) of3-(3-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)propionic acid in 20 ml.of benzene, 0.54 ml. (0.006 mole) of oxalyl chloride, 1 drop ofpyridine, 1 g. (0.003 mole) of1-isopropylsulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,and 0.43 ml. of triethylamine were substituted in the procedure ofExample 68, there was obtained 1.7 g., as an amorphous foam, of1-isopropylsulfonyl-2-amino-5(6)-[2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxyiminobenzyl]benzimidazole.

EXAMPLE 711-Dimethylaminosulfonyl-2-amino-6-(α-hydroxy-α-methylbenzyl)benzimidazole

To a solution of 600 ml. of tetrahydrofuran and 21.7 ml. (60 mmole) ofmethyl magnesium bromide in diethyl ether, under nitrogen, was addeddropwise over 1 hour a solution of 4.1 g. (12 mmole) of1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 180 ml. oftetrahydrofuran. The mixture was refluxed for 5 hours, poured into iceand 1 N hydrochloric acid, extracted twice with diethyl ether, washedwith saturated sodium chloride, dried, and filtered to yield 2.9 g., asan amorphous solid, of1-dimethylaminosulfonyl-2-amino-6-(α-hydroxy-α-methylbenzyl)benzimidazole.m/e 360.

Analysis C₁₇ H₂₀ N₄ O₃ S MW 360. Calcd: C, 56.67; H, 5.59; N, 15.54.Found: C, 56.77; H, 5.46; N, 15.27.

EXAMPLE 721-Dimethylaminosulfonyl-2-amino-6-(α-methylenebenzyl)benzimidazole

Two grams (5.5 mmole) of1-dimethylaminosulfonyl-2-amino-6-(α-hydroxy-α-methylbenzyl)benzimidazolein 130 ml. of chloroform was reacted with 1.3 g. of p-toluenesulfonicacid. The solution was refluxed with stirring for 6 hours. The solutionwas then washed with saturated sodium carbonate, dried, and filtered toyield 1.7 g. of1-dimethylaminosulfonyl-2-amino-6-(α-methylenebenzyl)benzimidazole, m.p.201°-202° C.

Analysis C₁₇ H₁₈ N₄ O₂ S MW 342. Calcd: C, 59.63; H, 5.30; N, 16.36.Found: C, 59.67; H, 5.35; N, 16.07.

EXAMPLE 731-Dimethylaminosulfonyl-2-amino-6-(α-ethyl-α-hydroxybenzyl)benzimidazole

When the procedure of Example 71 was repeated using 100 ml.tetrahydofuran, 22.2 ml. (60 mmole) of ethyl magnesium bromide (2.7mmole/ml) in diethyl ether, and 4.1 g. of1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole, there wasobtained 3.2 g., as a foam, of1-dimethylaminoslfonyl-2-amino-6-(α-ethyl-α-hydroxybenzyl)benzimidazole.

High resolution mass spec. for C₁₈ H₂₂ N₄ O₃ S. Calcd: 374.14123 .Found: 374.141.

EXAMPLE 741-Dimethylaminosulfonyl-2-amino-6-(α-ethylidenebenzyl)benzimidazole

When the procedure of Example 72 was repeated using 1.2 g. (3.21 mmole)of1-dimethylaminosulfonyl-2-amino-6-(α-ethyl-α-hydroxybenzyl)benzimidazole,750 mg. of p-toluenesulfonic acid, and 100 ml. of chloroform, there wasobtained 388 mg. of1-dimethylaminosulfonyl-2-amino-6-(α-ethylidenebenzyl)benzimidazole,m.p. 200°-202° C. (dec.)

High resolution mass spec. for C₁₈ H₂₀ N₄ O₂ S.

Calcd: 356.13107. Found: 356.131.

EXAMPLE 75

70.7 Grams of1-dimethylaminosulfonyl-2-amino-6-(α-acetoxyiminobenzyl)benzimidazolewas dissolved in a mixture of 200 ml. ethanol and 150 ml. chloroform.The solution was concentrated by boiling to 300 ml. and allowed to standat room temperature overnight. The crystals which formed were filteredto yield 6.2 g. of1-dimethylaminosulfonyl-2-amino-6-(syn-α-acetoxyiminobenzyl)benzimidazole,m.p. 175°-179° C.

The filtrate from the above paragraph was condensed to 100 ml. andcooled. The crystals which formed were 8.25 g. of1-dimethylaminosulfonyl-2-amino-6-(anti-α-acetoxyiminobenzyl)benzimidazole,m.p. 190°-195° C.

EXAMPLE 76

When 1 g. of1-isopropylsulfonyl-2-amino-6-(α-hydroxyiminobenzyl)benzimidazole in 4ml. of dimethylsulfoxide was subjected to high pressure chromatographyusing 50:50 methanol:water in a reverse phase 2.5×50 cm. column(LP-1/C₁₈ silica gel which is a chemically modified silica gel known inthe art) with a pressure of 70-2000 psi., there was obtained 70 mg. of1-isopropylsulfonyl-2-amino-6-(anti-α-hydroxyiminobenzyl)benzimidazoleand 30 mg. of1-isopropylsulfonyl-2-amino-6-(syn-α-hydroxyiminobenzyl)benzimidazole.

EXAMPLE 771-Dimethylaminosulfonyl-2-amino-6-(α-isopropyl-α-hydroxybenzyl)benzimidazole

When the procedure of Example 71 was repeated using 4.1 g. (12 mmole) of1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 180 ml. oftetrahydrofuran, 100 ml. tetrahydrofuran, and 28.6 ml. (60 mmole) ofisopropyl magnesium chloride in 100 ml. of tetrahydrofuran, there wasobtained1-dimethylaminosulfonyl-2-amino-6-(α-isopropyl-α-hydroxybenzyl)benzimidazole,yield 65%.

EXAMPLE 781-Dimethylaminosulfonyl-2-amino-6-(α-isopropylidenebenzyl)benzimidazole

When the procedure of Example 72 was repeated using 1.2 g. (3.2 mmoles)of1-dimethylaminosulfonyl-2-amino-6-(α-isopropyl-α-hydroxybenzyl)benzimidazole,750 mg. of p-toluenesulfonic acid, and 100 ml. of chloroform, there wasobtained1-dimethylaminosulfonyl-2-amino-6-(α-isopropylidenbenzyl)benzimidazole.

We claim:
 1. A method of suppressing the growth of a virus whichcomprises adding to a medium in which the virus is growing anantivirally effective amount of a compound of the formula ##STR10##wherein: R₁ is thiazol-2-yl, 2-acetamido-4-methylthiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-methyl-1,3,4-thiadiazol-5-yl, or2-methylamino-1,3,4-thiadiazol-5-yl;R₂ is amino, formamido, acetamido,propionamido or butyramido; R₃ is hydroxy, C₂ -C₈ alkanoyloxy,phenylacetoxy, α-C₁ -C₇ alkyl-α-hydroxybenzyl or benzoyloxy; or1,3-dithiolan-2-yl, 1,3-dithian-2-yl, tetrazol-5-yl, 1-(C₁ -C₄ alkyl)tetrazol-5-yl, 1,3,4-oxoadiazol-2-yl, or 2-(C₁ -C₄ alkyl)oxadiazol-5-yl;or ##STR11## wherein R₆ is hydrogen, C₁ -C₇ alkyl,C₃ -C₇ cycloalkyl, (C₃-C₇ cycloalkyl) methyl, 1-(C₃ -C₇ cycloalkyl) ethyl, benzyl, phenyl orphenyl substituted by C₁ -C₄ alkyl, C₁ -C₄ alkoxy, chloro, bromo, iodo,nitro or trifluoromethyl; or Z═C(R₆)--, wherein Z is hydroxyimino, C₁-C₄ alkoxyimino, C₁ -C₄ acyloxyimino, benzyloxyimino, benzoyloxyimino,hydrazono, thiocarbamylhydrazono, carboxymethoxyimino,methoxycarbonylhydrazono, ethoxycarbonylhydrazono, carbamylhydrazono, C₁-C₄ alkoxycarbonylethylcarbonyloxyimino,benzyloxycarbonylaminomethylcarbonyloxyimino,p-nitrobenzyloxycarbonylethylcarbonyloxyimino,phthalimidomethylcarbonyloxyimino,2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxyimino orC₁ -C₇ alkylidene; and R₃ is at the 5 or 6 position.
 2. The method ofclaim 1 employing the compound wherein R₃ is ##STR12##
 3. The method ofclaim 2 employing the compound wherein R₁ is thiazol-2-yl or2-acetamido-4-methylthiazol-5-yl.
 4. The method of claim 3 employing thecompound wherein R₂ is amino.
 5. The method of claim 1 employing thecompound wherein R₃ is Z═C(R₆)--.
 6. The method of claim 5 employing thecompound wherein R₁ is thiazol-2-yl or 2-acetamido-4-methylthiazol-5-yl.7. The method of claim 6 employing the compound wherein R₂ is amino. 8.The method of claim 7 employing the compound ethyl1-(2-acetamido-4-methylthiazol-5-ylsulfonyl)-2-amino-5(6)benzimidazolecarboxylate.
 9. The method of claim 7employing the compound ethyl 1-(thiazol-2-yl sulfonyl)-2-amino-5(6)benzimidazolecarboxylate.
 10. A method of suppressing the growth of avirus which comprises administering intranasally to a warm-bloodedanimal infected with the virus an antivirally effective amount of acompound of the formula ##STR13## wherein: R₁ is thiazol-2-yl,2-acetamido-4-methylthiazol-5-yl, 1,3,4-thiadiazol-2-yl,2-methyl-1,3,4-thiadiazol-5-yl, or2-methylamino-1,3,4-thiadiazol-5-yl;R₂ is amino, formamido, actamido,propionamido or butyramido; R₃ is hydroxy, C₂ -C₈ alkanoyloxy,phenylacetoxy, α-C₁ -C₇ alkyl-α-hydroxybenzyl or benzoyloxy; or1,3-dithiolan-2-yl, 1,3-dithian-2-yl, tetrazol-5-yl, 1-(C₁ -C₄ alkyl)tetrazol-5-yl, 1,3,4-oxoadiazol-2-yl, or 2-(C₁ -C₄ alkyl)oxadiazol-5-yl;or ##STR14## wherein R₆ is hydrogen, C₁ -C₇ alkyl,C₃ -C₇ cycloalkyl, (C₃-C₇ cycloalkyl) methyl, 1-(C₃ -C₇ cycloalkyl) ethyl, benzyl, phenyl orphenyl substituted by C₁ -C₄ alkyl, C₁ -C₄ alkoxy, chloro, bromo, iodo,nitro or trifluoromethyl; or Z═C(R₆)--, wherein Z is hydroxyimino, C₁-C₄ alkoxyimino, C₁ -C₄ acyloxyimino, benzyloxyimino, benzoyloxyimino,hydrazono, thiocarbamylhydrazono, carboxymethoxyimino,methoxycarbonylhydrazono, ethoxycarbonylhydrazono, carbamylhydrazono, C₁-C₄ alkoxycarbonylethylcarbonyloxyimino,benzyloxycarbonylaminomethylcarbonyloxyimino,p-nitrobenzyloxycarbonylethylcarbonyloxyimino,phthalimidomethylcarbonyloxyimino,2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxyimino orC₁ -C₇ alkylidene; and R₃ is at the 5 or 6 position.
 11. The method ofclaim 10 employing a compound wherein R₃ is ##STR15##
 12. The method ofclaim 11 employing a compound wherein R₁ is thiazol-2-yl or2-acetamdio-4-methylthiazol-5-yl.
 13. The method of claim 12 employing acompound wherein R₂ is amino.
 14. The method of claim 10 employing acompound wherein R₃ is Z═C(R₆)--.
 15. The method of claim 14 employing acompound wherein R₁ is thiazol-2-yl or 2-acetamido-4-methylthiazol-5-yl.16. The method of claim 15 employing a compound wherein R₂ is amino. 17.A pharmaceutical formulation useful in the treatment of viral infectionscomprising a compound of the formula ##STR16## wherein: R₁ isthiazol-2-yl, 2-acetamido-4-methylthiazol-5-yl, 1,3,4-thiadiazol-2-yl,2-methyl-1,3,4-thiadiazol-5-yl, or2-methylamino-1,3,4-thiadiazol-5-yl;R₂ is amino, formamido, acetamido,propionamido or butyramido; R₃ is hydroxy, C₂ -C₈ alkanoyloxy,phenylacetoxy, α-C₁ -C₇ alkyl-α-hydroxybenzyl or benzoyloxy; or1,3-dithiolan-2-yl, 1,3-dithian-2-yl, tetrazol-5-yl, 1-(C₁ -C₄ alkyl)tetrazol-5-yl, 1,3,4-oxadiazol-2-yl, or 2-(C₁ -C₄ alkyl)oxadiazol-5-yl;or ##STR17## wherein R₆ is hydrogen, C₁ -C₇ alkyl,C₃ -C₇ cycloalkyl, (C₃-C₇ cycloalkyl) methyl, 1-(C₃ -C₇ cycloalkyl) ethyl, benzyl, phenyl orphenyl substituted by C₁ -C₄ alkyl, C₁ -C₄ alkoxy, chloro, bromo, iodo,nitro or trifluoromethyl; or Z═C(R₆)--, wherein Z is hydroxyimino, C₁-C₄ alkoxyimino, C₁ -C₄ acyloxyimino, benzyloxyimino, benzoyloxyimino,hydrazono, thiocarbamylhydrazono, carboxymethoxyimino,methoxycarbonylhydrazono, ethoxycarbonylhydrazono, carbamylhydrazono, C₁-C₄ alkoxycarbonylethylcarbonyloxyimino,benzyloxycarbonylaminomethylcarbonyloxyimino,p-nitrobenzyloxycarbonylethylcarbonyloxyimino,phthalimidomethylcarbonyloxyimino,2-(2-benzyloxycarbonyl-5-oxoisoxazolidin-4-yl)ethylcarbonyloxyimino orC₁ -C₇ alkylidene; and R₃ is at the 5 or 6 position in combination witha pharmaceutical diluent or carrier therefor.
 18. The formulation ofclaim 17 employing a compound wherein R₂ is amino.
 19. The formulationof claim 18 employing a compound wherein R₁ is thiazole-2-yl or2-acetamido-4-methylthiazol-5-yl.
 20. The formulation of claim 19employing a compound wherein R₃ is ##STR18##
 21. The formulation ofclaim 19 employing a compound wherein R₃ is Z═C(R₆).